Naphthyl-benzoxazepines or -benzothiazepines as squalene synthetase inhibitors

ABSTRACT

This invention relates to certain benzoxazepinones and benzothiazepinones useful as hypocholesterolemic agents and antiatheroscierosis agents.

This application was filed under 35 U.S.C. §371 based on PCT/IB95/00424,which was filed on Jun. 2, 1995 which is a continuation of U.S.application Ser. No. 08/362,713 which was filed on Dec. 23, 1994 and isnow abandoned.

BACKGROUND OF THE INVENTION

This invention relates to cholesterol synthesis inhibitors,pharmaceutical compositions containing such inhibitors and the use ofsuch inhibitors to treat hypercholesterolemia and atherosclerosis inmammals.

Plasma cholesterol levels have been positively correlated with theincidence of clinical events associated with coronary heart disease(CHD). Thus, pharmacological interventions that reduce cholesterollevels in mammals have a beneficial effect on CHD. In particular,decreased plasma low density lipoprotein (LDL) cholesterol levels areassociated with decreased atherosclerosis and a decreased risk of CHD,and hypolipidemic agents used in either monotherapy or combinationtherapy are effective at reducing plasma LDL cholesterol levels and thesubsequent risk of CHD.

Cholesterol metabolism in mammals involves a series of pathwaysincluding cholesterol absorption in the small intestine, cholesterolbiosynthesis in numerous tissues (primarily the liver and smallintestine), bile acid biosynthesis in the liver and reabsorption in thesmall intestine, synthesis of cholesterol-containing plasma lipoproteinsby the liver and intestine, catabolism of the cholesterol-containingplasma lipoproteins by the liver and extrahepatic tissues and secretionof cholesterol and bile acids by the liver.

Cholesterol synthesis occurs in multiple tissues, but principally in theliver and the intestine. It is a multistep process starting fromacetyl-coenzyme A catalyzed by a series of enzymes includinghydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase, HMG-CoA synthase,squalene synthetase, squalene epoxidase, squalene cyclase and lanosteroldemethylase. Inhibition of catalysis of these enzymes or blockingHMG-CoA reductase gene expression is recognized as an effective means toreduce cholesterol biosynthesis (thus they are referred to ascholesterol synthesis inhibitors) and can lead to a reduction incholesterol levels. For example, there are known HMG-CoA reductaseinhibitors (e.g., lovastatin, simvastatin, pravastatin, fluvastatin)that are used for the treatment of hypercholesterolemia.

Recently adopted National Cholesterol Education Program guidelinesrecommend aggressive lipid-lowering therapy for patients withpre-existing cardiovascular disease or for those with multiple factorsthat place them at increased risk.

The term squalene synthetase inhibitor refers to compounds that inhibitthe condensation of 2 molecules of farnesylpyrophosphate to formsqualene, a reaction that is catalyzed by the enzyme squalenesynthetase. Such inhibition is readily determined by those skilled inthe art according to standard assays (Meth. Enzymol. 1969; 15: 393-454and Meth. Enzymol. 1985; 110:359-373 and references contained therein).A summary of squalene synthetase inhibitors has been compiled (Curr. Op.Ther. Patents (1993) 861-4). European patent publication 0 567 026 A1discloses 4,1-benzoxazepine derivatives as squalene synthase inhibitorsand their use in the treatment of hypercholesterolemia and asfungicides. European patent publication 0 645 378 A1 discloses condensedseven- or eight-membered heterocycles as squalene synthetase inhibitorsand their use in treatment and prevention of hypercholesterolemia andfungal infections. European patent publication 0 645 377 A1 disclosesbenzoxazepine derivatives as squalene synthetase inhibitors useful forthe treatment of hypercholesterolemia or coronary sclerosis. Europeanpatent publication 0 611 749 A1 discloses substituted amic acidderivatives useful for treatment of arteriosclerosis.

Thus, although there are a variety of hypercholesterolemia therapies,there is a continuing need and a continuing search in this field of artfor alternative therapies.

SUMMARY OF THE INVENTION

This invention is directed to cholesterol synthesis inhibitor compoundsof Formula I useful for the treatment of hypercholesterolemia andatherosclerosis.

The compounds of this invention have the formula ##STR1## and thepharmaceutically acceptable cationic and anionic salts, prodrugs andstereoisomers thereof

wherein X is oxy, thio, --S(O)-- or --S(O)₂ --;

Y is carbonyl or methylene;

R₁, R₂, R₃ and R₉ are each independently hydrogen, halo, hydroxyl,trifluoromethyl, (C₁ -C₄)alkyl, fluorinated (C₁ -C₄)alkyl having from 1to 9 fluorines, (C₁ -C₄)alkoxy, fluorinated (C₁ -C₄)alkoxy having from 1to 9 fluorines, (C₁ -C₄)alkylthio, (C₁ -C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl, phenyl, amino, mono-N- or di-N,N-(C₁ -C₄)alkylamino,carboxyl, (C₁ -C₄)alkoxylcarbonyl, carbamoyl, mono-N- or di-N,N-(C₁-C₄)alkylcarbamoyl, (C₁ -C₄)alkanoylamino, fluorinated (C₁-C₄)alkanoylamino having from 1 to 9 fluorines, (C₁-C₄)alkylsulfonylamino or fluorinated (C₁ -C₄)alkylsulfonylamino havingfrom 1 to 9 fluorines, (C₁ -C₆)alkanoyl, (C₁ -C₄)alkanoyl(C₁ -C₆)alkyl,oxazolyl, thiazolyl, isoxazolyl, pyrazolyl or isothiazolyl wherein saidpreceding heterocycles are carbon linked and wherein R₁ and R₂ can betaken together to form a five, six or seven membered carbocyclic ring orcan be taken together to form methylenedioxyl, ethylenedioxyl orpropylenedioxyl and such rings formed by taking R₁ and R₂ together arefused at the 7 and 8 positions;

R₄ is (C₁ -C₇)alkyl or (C₃ -C₄)cycloalkylmethyl;

Z is carboxyl, (C₁ -C₄)alkoxycarbonyl, aminocarbonyl, cyano,hydroxyaminocarbonyl, --C(O)N(H)SO₂ R₅, tetrazol-5-yl,4,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl, tetrazol-5-yl-aminocarbonyl,3-oxoisoxazolidin-4-yl-aminocarbonyl, ##STR2## R₅ is amino or mono-N- ordi-N,N-(C₁ -C₄)alkylamino; (C₁ -C₄)alkyl optionally substituted with 1to 9 fluorines, amino, mono-N- or di-N,N-(C₁ -C₄)alkylamino, carboxyl,(C₁ -C₄)alkoxycarbonyl, carbamoyl or mono-N- or di-N,N-(C₁-C₄)alkylcarbamoyl; phenyl optionally mono- or di-substitutedindependently with methyl, methoxyl, fluoro, trifluoromethoxyl,carboxyl, (C₁ -C₄)alkoxycarbonyl, methylthio, methylsulfinyl,methylsulfonyl, (C₁ -C₄)alkylsulfonylamino or mono-N- or di-N,N-(C₁-C₄)alkylaminosulfonyl; or thiazolyl, isothiazolyl, thienyl, furyl,pyridinyl or such heterocycles optionally mono-substituted by carboxyl,or mono- or di-substituted with methyl;

R₆ is hydrogen, hydroxyl or methoxyl;

T forms a five to seven membered mono-aza, saturated ring, said ringoptionally containing thio and said ring optionally mono-substituted oncarbon with hydroxyl;

U forms a three to seven membered saturated carbocyclic ring;

V is --CO₂ R₇, aminocarbonyl, cyano, tetrazol-5-yl,4,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl, tetrazol-5-yl-aminocarbonyl or3-oxoisoxazolidin-4-yl-aminocarbonyl;

R₇ is hydrogen or (C₁ -C₄)alkyl;

p is 1, 2, 3or 4;

R₈ is hydroxyl, thiol, carboxyl, (C₁ -C₄)alkoxycarbonyl, carbamoyl,amino, sulfamoyl, (C₁ -C₄)alkoxy, fluorinated (C₁ -C₄)alkoxy having from1 to 9 fluorines, (C₁ -C₄)alkylthio, (C₁ -C₄)alkylsulfonyl, (C₁-C₄)alkylsulfinyl, mono-N- or di-N,N-(C₁ -C₄)alkylcarbamoyl, mono-N- ordi-N,N-(C₁ -C₄)alkylamino, (C₁ -C₄)alkylsulfonylamino, fluorinated (C₁-C₄)alkylsulfonylamino having from 1 to 9fluorines, (C₁-C₄)alkanoylamino, fluorinated (C₁ -C₄)alkanoylamino having from 1 to 9fluorines, mono-N- or di-N,N-(C₁ -C₄)alkylaminosulfonyl, ureido, mono-N-or di-N,N-(C₁ -C₄)ureido, imidazolyl or pyridyl; and

W is pyridyl, pyrimidyl, 1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl,thiazolyl, 1,3,4-triazolyl or oxazolyl.

A first group of preferred compounds of Formula I consists of thosecompounds wherein

R₁, R₂, R₃ and R₉ are each independently hydrogen, halo, hydroxyl,trifluoromethyl, (C₁ -C₄)alkyl, fluorinated (C₁ -C₄)alkyl having from 1to 9 fluorines, (C₁ -C₄)alkoxy, fluorinated (C₁ -C₄)alkoxy having from 1to 9 fluorines, (C₁ -C₄)alkylthio, (C₁ -C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl, phenyl, amino, mono-N- or di-N,N-(C₁ -C₄)alkylamino,carboxyl, (C₁ -C₄)alkoxycarbonyl, carbamoyl, mono-N- or di-N,N-(C₁-C₄)alkylcarbamoyl, (C₁ -C₄)alkanoylamino, fluorinated (C₁-C₄)alkanoylamino having from 1 to 9 fluorines, (C₁-C₄)alkylsulfonylamino or fluorinated (C₁ -C₄)alkylsulfonylamino havingfrom 1 to 9 fluorines, wherein R₁ and R₂ can be taken together to form afive, six or seven membered carbocyclic ring or can be taken together toform methylenedioxyl, ethylenedioxyl or propylenedioxyl and such ringsformed by taking R₁ and R₂ together are fused at the 7 and 8 positions;

Z is carboxyl, (C₁ -C₄)alkoxycarbonyl, hydroxyaminocarbonyl,--C(O)N(H)SO₂ R₅, tetrazol-5-yl, 4,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl,tetrazol-5-yl-aminocarbonyl, 3-oxoisoxazolidin-4-yl-aminocarbonyl,##STR3## T forms a five to seven membered mono-aza, saturated ringoptionally substituted with hydroxyl; and

V is --CO₂ R₇, tetrazol-5-yl, 4,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl,tetrazol-5-yl-aminocarbonyl or 3-oxoisoxazolidin-4-yl-aminocarbonyl.

Within this first group of preferred compounds of Formula I is a firstgroup of especially preferred compounds wherein

the C³ and C⁵ substituents are trans;

R₁ and R₂ are each independently hydrogen, halo, (C₁ -C₄)alkyl, (C₁-C₄)alkoxy, hydroxy, trifluoromethyl, (C₁ -C₄)alkylthio, fluorinated (C₁-C₄)alkoxy having from 1 to 9 fluorines, (C₁ -C₄)alkanoyl or R₁ and R₂taken together form an ethylenedioxy ring;

R₃ and R₉ are H;

X is oxy;

Y is carbonyl;

V is --CO₂ R₇ ; and

Z is carboxyl, tetrazol-5-yl, ##STR4##

Within the preceding first group of especially preferred compounds is afirst group of particularly preferred compounds wherein

R₁ and R₂ are each independently hydrogen, halo, (C₁ -C₄)alkyl, (C₁-C₄)alkoxy, hydroxy or trifluoromethyl; and

Z is carboxyl, ##STR5##

Preferred within the immediately preceding particularly preferredcompounds are compounds wherein

T forms a piperidin-1-yl ring; and

R₈ is carboxyl or alkylthio.

Particular compounds within the immediately preceding group arecompounds wherein:

a. R₄ is neopentyl;

R₁ is 7-chloro;

R₂ is H; and

Z is carboxyl;

b. R₄ is neopentyl;

R₁ is 7-chloro;

R₂ is H; and

Z is 4-carboxylpiperidin-1 -yl-carbonyl;

c. R₄ is neopentyl;

R₁ is 7-chloro;

R₂ is H; and

Z is 3-carboxylpiperidin-1-yl-carbonyl;

d. R₄ is neopentyl;

R₁ is 7-chloro;

R₂ is H;

V is --CO₂ R₇ ;

Z is ##STR6## R₇ is methyl; R₈ is carboxyl; and

p is 1;

e. R₄ is neopentyl;

R₁ is 7-chloro;

R₂ is H;

V is -CO₂ R₇ ;

Z is ##STR7## R₇ is methyl; R₈ is carboxyl; and

p is 2;

f. R₄ is neopentyl;

R₁ is 7-chloro;

R₂ is H;

V is --CO₂ R₇ ;

Z is ##STR8## R₇ is H; R₈ is thiomethyl; and

p is 1; or

g. R₄ is neopentyl;

R₁ is 7-chloro;

R₂ is H; and

Z is 4-ethoxycarbonylpiperidin-1-yl-carbonyl.

Especially preferred trans stereoisomers are

(-)-trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-aceticacid,

(-)-N-(trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl)-isonipecoticacid,

(-)-N-(trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl)-nipecoticacid,

(-)-N-trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl!-(-)-nipecoticacid,

(-)-N-(trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl)-L-asparticacid-α-methyl ester,

(-)-N-(trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl)-L-glutamic-α-methylester,

(-)-N-(trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl)-L-S-methylcysteineand

Ethyl ester of(-)-N-trans-(7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl)-isonipecoticacid.

Other preferred compounds are

N-trans-7-trifluoromethyl-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl!isonipecoticacid,

N-trans-7-trifluoromethyl-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl!nipecoticacid,

N-trans-7-trifluoromethyl-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl!-L-proline,

trans-7-methyl-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-aceticacid,

N-trans-7-methyl-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-acetyl!isonipecoticacid,

N-trans-7-methyl-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-acetyl!nipecoticacid,

trans-7-methoxy-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-aceticacid,

N-trans-7-methoxy-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-acetyl!isonipecoticacid and

N-trans-7-methoxy-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-acetyl!nipecoticacid.

Another group of preferred stereoisomers is

(-)-trans-7-trifluoromethyl-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-aceticacid,

(-)-N-trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl!-L-pipecolinicacid and

(-)-N-trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl)-L-methionine.

Yet another group of preferred compounds is

trans-7-methylthio-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-aceticacid,

trans-7-trifluoromethoxy-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-aceticacid,

trans-7,8ethylenedioxy-5-(l-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-aceticacid,

N-trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl!-1-amino-1-cyclopentanecarboxylicacid,

N-trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl!-1-amino-1-cyclopropanecarboxylicacid and

N-trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl!-4-azetidinecarboxylicacid.

Within the above first group of especially preferred compounds is asecond group of particularly preferred compounds wherein

T forms a 1,3-thiazolidine ring.

Preferred within this group of compounds is

(-)-N-trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepin-3-acetyl!-(R)-thiazolidine-4-carboxylicacid.

Within the above first group of particularly preferred compounds arecompounds wherein

T forms a pyrrolidin-1-yl ring.

Within the immediately preceding group of compounds is a compoundwherein

R₄ is neopentyl;

R₁ is 7-chloro;

R₂ is H; and

Z is L-proline-N-carbonyl or D-proline-N-carbonyl,

and two preferred stereoisomers thereof are

(-)-N-(trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl)-L-prolineand

(-)-N-trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl!-D-proline.

Within the first group of preferred compounds of Formula I is a secondgroup of especially preferred compounds wherein

the C³ and C⁵ substituents are trans;

R₁ and R₂ are each independently hydrogen, halo, (C₁ -C₄)alkyl, (C₁-C₄)alkoxy, hydroxy or trifluoromethyl;

R₃ and R₉ are H;

X is oxy;

Y is methylene;

V is --CO₂ R₇ ; and

Z is carboxyl, ##STR9##

Within the above second group of especially preferred compounds is afirst group of particularly preferred compounds wherein

Z is ##STR10## and T forms a piperidin-1-yl ring.

Particular compounds within the immediately preceding group arecompounds wherein:

a. R₄ is neopentyl;

R₁ is 7-chloro;

R₂ is H; and

Z is 3-carboxylpiperidin-1-yl-carbonyl; and

b. R₄ is neopentyl;

R₁ is 7-chloro;

R₂ is H; and

Z is 4-carboxylpiperidin-1-yl-carbonyl.

Particular stereoisomers of the immediately preceding compounds are

(-)-N-(trans-7-chloro-5-(1-naphthyl)-1-neopentyl-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl)-nipecoticacid and

(-)-N-(trans-7-chloro-5-(1-naphthyl)-1-neopentyl-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl)-isonipecoticacid.

Within the above first group of preferred compounds of Formula I is athird group of especially preferred compounds wherein

the C³ and C⁵ substituents are trans;

R₁ and R₂ are each independently hydrogen, halo, (C₁ -C₄)alkyl, (C₁-C₄)alkoxy, hydroxy, trifluoromethyl, (C₁ -C₄)alkylthio, fluorinated (C₁-C₄)alkoxy having from 1 to 9 fluorines, (C₁ -C₄)alkanoyl or R₁ and R₂taken together form an ethylenedioxy ring;

R₃ and R₉ are H;

X is thio;

Y is carbonyl;

V is --CO₂ R₇ or tetrazol-5-yl; and

Z is carboxyl, tetrazol-5-yl, ##STR11##

Within the above third group of especially preferred compounds arecompounds wherein

T forms a piperidin-1-yl ring.

Particular compounds within the immediately preceding group are

trans-7-acetyl-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzothiazepine-3-aceticacid,

N-trans-7-acetyl-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzothiazepine-3-acetyl!isonipecoticacid,

trans-7-chloro-5-(naphthalen-1-yl)-1-neopentyl-3-(1H-tetrazol-5-ylmethyl)-1,2,3,5-tetrahydro-4,1-benzothiazepin-2-oneand

trans-7-chloro-5-(naphthalen-1-yl)-1-neopentyl-3-{2-oxo-2-4-(1H-tetrazol-5-yl)-piperidin-1-yl!-ethyl}-1,2,3,5-tetrahydro4,1-benzothiazepin-2-one.

Within the first group of preferred compounds of Formula I is a fourthgroup of especially preferred compounds wherein

the C³ and C⁵ substituents are trans;

R₁ and R₂ are each independently hydrogen, halo, (C₁ -C₄)alkyl, (C₁-C₄)alkoxy, hydroxy or trifluoromethyl;

R₃ and R₉ are H;

X is thio;

Y is carbonyl;

V is CO₂ --R₇ ; and

Z is carboxyl, ##STR12##

Within the fourth group of especially preferred compounds is a firstgroup of particularly preferred compounds wherein

T forms a piperidin-1-yl ring.

Within the immediately preceding group of compounds are

trans-7-methyl-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzothiazepine-3-aceticacid,

N-trans-7-methyl-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzothiazepine-3-acetyl!isonipecoticacid,

N-trans-7-methyl-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzothiazepine-3-acetyl!nipecoticacid,

trans-7-methoxy-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzothiazepine-3-aceticacid and

N-trans-7-methoxy-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzothiazepine-3-acetyl!isonipecoticacid.

Other compounds within the immediately preceding first group ofparticularly preferred compounds, which is within the fourth group ofespecially preferred compounds, are compounds wherein T forms apiperidin-1-yl ring and

a. R₄ is neopentyl;

R₁ is 7-chloro;

R₂ is H; and

Z is 3-carboxylpiperidin-1-yl-carbonyl;

b. R₄ is neopentyl;

R₁ is 7-chloro;

R₂ is H; and

Z is 4-ethoxycarbonylpiperidin-1-yl-carbonyl; or

c. R₄ is neopentyl;

R₁ is 7-chloro;

R₂ is H; and

Z is 4-carboxylpiperidin-1-yl-carbonyl; and preferred stereoisomersthereof are

(-)-N-(trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepin-3-acetyl)-nipecoticacid,

Ethyl ester of(-)-N-(trans-7-chloro-5-naphthyl-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepin-3-acetyl)isonipecoticacid, or

(-)-N-(trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepin-3-acetyl)-isonipecoticacid.

Within the fourth group of especially preferred compounds is anothercompound wherein

R₄ is neopentyl;

R₁ is 7-chloro;

R₂ is H; and

Z is carboxyl,

and a stereoisomer thereof

(-)-trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepin-3-aceticacid,

and (R)-α-methylbenzylammonium salt thereof.

Within the fourth group of especially preferred compounds are compoundswherein

a. R₄ is neopentyl;

R₁ is 7-chloro;

R₂ is H;

V is --CO₂ R₇ ;

Z is ##STR13## R₇ is methyl; R₈ is carboxyl; and

p is 2;

b. R₄ is neopentyl;

R₁ is 7-chloro;

R₂ is H;

V is --CO₂ R₇ ;

Z is ##STR14## R₇ is methyl; R₈ is carboxyl; and

p is 1; and

c. R₄ is neopentyl;

R₁ is 7-chloro;

R₂ is H;

V is --CO₂ R₇ ;

Z is ##STR15## R₇ is H; R₈ is thiomethyl; and

p is 1.

Within the immediately preceding group are the stereoisomers

(-)-N-(trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepin-3-acetyl)-L-glutamicacid-α-methyl ester,

(-)-N-(trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepin-3-acetyl)-L-asparticacid-α-methyl ester or

(-)-N-(trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepin-3-acetyl)-L-S-methylcysteine.

Within the fourth group of especially preferred compounds are compoundswherein

T forms a pyrrolidin-1-yl ring.

Within the immediately preceding group of compounds is a compoundwherein

R₄ is neopentyl;

R₁ is 7-chloro;

R₂ is H; and

Z is L-proline-N-carbonyl or D-proline-N carbonyl and the stereoisomersthereof

(-)-N-(trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepin-3-acetyl)-L-prolineand

(-)-N-trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepin-3-acetyl!-D-proline.

Within the first group of preferred compounds is a fifth group ofespecially preferred compounds wherein

the C³ and C⁵ substituents are trans;

R₁ and R₂ are each independently hydrogen, halo, (C₁ -C₄)alkyl, (C₁-C₄)alkoxy, hydroxy, trifluoromethyl, (C₁ -C₄)alkylthio, fluorinated (C₁-C₄)alkoxy having from 1 to 9 fluorines, (C₁ -C₄)alkanoyl or R₁ and R₂taken together form an ethylenedioxy ring;

R₃ is H;

R₉ is (C₁ -C₄)alkoxy

X is oxy;

Y is carbonyl;

V is --CO₂ R₇ ; and

Z is carboxyl, tetrazol-5-yl, ##STR16##

Within the fifth group of especially preferred compounds are compoundswherein

R₁ is 7-chloro;

R₂ is H;

R₄ is neopentyl;

R₉ is methoxy; and

T forms a piperidin-1-yl ring.

Within the immediately preceding group are the compounds

trans-7-chloro-5-(4-methoxynaphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-aceticacid;

N-trans-7-chloro-5-(4-methoxynaphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-acetyl!isonipecoticacid; or

N-trans-7-chloro-5-(4-methoxynaphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-acetyl!nipecoticacid.

Yet another aspect of this invention is directed to a method fortreating hypercholesterolemia, atherosclerosis, fungal infections,Alzheimer's or acne in a mammal by administering to a mammal sufferingfrom hypercholesterolemia, atherosclerosis, a fungal infection,Alzheimer's or acne a hypercholesterolemia, atherosclerosis, antifungal,Alzheimer's or acne treating amount of a Formula I compound.

This invention is also directed to pharmaceutical compositions for thetreatment of hypercholesterolemia, atherosclerosis, fungal infections,Alzheimer's or acne in mammals which comprise a therapeuticallyeffective amount of a compound of the Formula I and a pharmaceuticallyacceptable carrier.

Exemplary T rings are piperidin-1-yl, pyrrolidin-1-yl, thiazolidin-3-yl,azetidin-1-yl, tetrahydro-1,4-thiazin-4-yl, tetrahydro-1,4-oxazin-4-yland tetrahydro-1,3-thiazin-3-yl.

Exemplary U rings are cyclopropyl, cyclobutyl, cyclopentyl andcyclohexyl.

By halo is meant chloro, bromo, iodo, or fluoro.

By alkyl is meant straight chain or branched saturated hydrocarbon.

The expression "pharmaceutically-acceptable anionic salt" refers tonontoxic anionic salts containing anions such as (but not limited to)chloride, bromide, iodide, sulfate, bisulfate, phosphate, acetate,maleate, fumarate, oxalate, lactate, tartrate, citrate, gluconate and4-toluene-sulfonate.

The expression "pharmaceutically-acceptable cationic salt" refers tonontoxic cationic salts such as (but not limited to) sodium, potassium,calcium, magnesium, ammonium or protonated benzathine(N,N'-dibenzylethylenediamine), choline, ethanolamine, diethanolamine,ethylenediamine, L-lysine, L-arginine, meglamine (N-methyl-glucamine),benethamine (N-benzylphenethylamine), piperazine or tromethamine(2-amino-2-hydroxymethyl-1,3-propanediol). This is meant to include(R)-α-methylbenzylammonium.

The expression "prodrug" refers to compounds that are drug precursors,which following administration and absorption, release the drug in vivovia some metabolic process. Exemplary prodrugs upon cleavage release thecorresponding free acid, and such hydrolyzable ester-forming residues ofthe Formula I compounds include but are not limited to substituentswherein the Z or the V moiety is carboxyl and the free hydrogen isreplaced by (C₁ -C₄)alkyl, (C₂ -C₇)alkanoyloxymethyl,1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms,1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms,alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms,1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms,1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms,N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms,3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N-(C₁-C₂)alkylamino(C₂ -C₃)alkyl (such as β-dimethylaminoethyl),carbamoyl-(C₁ -C₂)alkyl, N,N-di(C₁ -C₂)alkylcarbamoyl-(C₁ -C₂)alkyl andpiperidino-, pyrrolidino- or morpholino(C₂ -C₃)alkyl.

As used herein, the expression "reaction-inert solvent" refers to asolvent which does not interact with starting materials, reagents,intermediates or products in a manner which adversely affects the yieldof the desired product.

The parenthetical negative or positive sign used herein in thenomenclature denotes the direction plane polarized light is rotated bythe particular stereoisomer.

Other features and advantages will be apparent from the specificationand claims which describe the invention.

DETAILED DESCRIPTION OF THE INVENTION ##STR17##

According to Reaction Scheme I the desired Formula I compounds whereinR₁, R₂, R₃, R₄ and R₉ are as described above, X is oxy, Y is carbonyl ormethylene and Z is a substituted amide (depicted as Formula IIcompounds) may be prepared by acylating the appropriate amine with thecorresponding Formula III compound wherein Z is carboxyl.

Generally, the acid is combined with the appropriate amine In an aproticsolvent such as dimethylformamide in the presence of an amine base suchas triethylamine and a coupling agent such as diethyl cyanophosphonateor propylphosphonic anhydride at a temperature of about 0° C. to about40° C. for about 1 hour to about 6 hours.

Alternatively, the acid is combined with the appropriate amine in thepresence of a carbodiimide (e.g.,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride) in areaction inert solvent such as methylene chloride at a temperature ofabout 10° C. to 40° C. for about 2 to about 24 hours.

The desired Formula I compound wherein Z or V is tetrazol-5-yl may beprepared from the corresponding Formula I compound wherein Z or V iscarboxyl by converting the carboxyl group to a carboxamide group (Z orV=CONH₂), dehydrating the carboxamide to the nitrile (Z or V=CN) andreacting the nitrile with an appropriate azide to form the tetrazolegroup.

Generally, the acid is converted to the imidazolide by reaction withcarbonyl diimidazole in an aprotic solvent such as methylene chloride ata temperature of 15° C. to about 40° C. for about 30 minutes to about 4hours, conveniently at room temperature for 1 hour. The resultingimidazolide is converted to the corresponding amide by bubbling ammoniagas into the reaction mixture at a temperature of 10° C. to about 40° C.for about 3 minutes to about 30 minutes, preferably at room temperaturefor about 5 minutes or until the reaction is complete by TLC analysis.The amide is converted to the nitrile by treatment with trifluoroaceticanhydride and triethylamine in an inert solvent such as methylenechloride at 0° C. for about 25 minutes to 2 hours, preferably 30minutes. Treatment of the nitrile with sodium azide and ammoniumchloride in dimethylformamide at a temperature of about 90° C. to about130° C. for about 7 hours to about 60 hours, preferably at a temperatureof 120° C. for 24 hours, yields the desired tetrazole.

The desired Formula I compound wherein Z or V is4,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl may be prepared from thecorresponding Formula I compound wherein Z or V is CN by converting thenitrile to the amide oxime and reacting the amide oxime with acarbonylating agent to form the corresponding4,5-dihydro-5-oxo-1,2,4-oxadiazole derivative.

Generally, the nitrile is converted to the amide oxime by reaction withhydroxylamine hydrochloride in the presence of a base such as potassiumcarbonate in an alcoholic solvent at a temperature of about 60° C. toabout 110° C. for about 5 hours to 24 hours, preferably in refluxingethanol for about 18 hours. The amide oxime is converted to thecorresponding 4,5-dihydro-5-oxo-1,2,4-oxadiazole derivative by reactionwith carbonyidiimidazole and triethylamine in refluxing ethyl acetatefor 24 hours.

Prodrugs of Formula I compounds having a carboxyl group may be preparedby combining the acid with the appropriate alkyl halide in the presenceof a base such as potassium carbonate in an inert solvent such asdimethylformamide at a temperature of about 15° C. to about 100° C. forabout 1 hour to about 24 hours.

Alternatively, the acid is combined with the appropriate alcohol assolvent in the presence of a catalytic amount of acid such asconcentrated sulfuric acid at a temperature of about 20° C. to about120° C., preferably at reflux, for about 1 hour to about 24 hours.

The desired Formula III compounds wherein R₁, R₂, R₃, R₄ and R₉ are asdescribed above, X is oxy, Y is carbonyl or methylene and Z is carboxylmay be prepared from the corresponding Formula IV compound bycyclization followed by hydrolysis. Alternatively, the hydrolysis stepmay be omitted resulting in the desired prodrugs.

Generally, the Formula IV compound is combined with a base such aspotassium carbonate in an alcoholic solvent such as ethanol at atemperature of about 10° C. to about 40° C., preferably ambient, forabout 2 hours to about 18 hours followed by hydrolysis in an aqueousalcoholic solvent such as methanol/water with a base such as potassiumcarbonate at a temperature of about 40° C. to about 80° C., preferablyat reflux, for about 2 hours to about 18 hours.

The desired Formula IV compounds wherein R₁, R₂, R₃, R₄ and R₉ are asdescribed above, X is oxy, Y is carbonyl or methylene and P is a knowncarboxyl protecting group (see reference below) may be prepared from theappropriate corresponding Formula V compound by acylation or alkylationas appropriate.

Generally, for those compounds wherein Y is carbonyl the appropriateFormula V compound is combined with the appropriate fumaryl chlorideprotected mono acid, such as fumaryl chloride monoalkyl ester, in areaction-inert solvent such as methylene chloride at a temperature ofabout 10° C. to about 50° C., typically ambient, for about six to abouteighteen hours. Generally, for those compounds wherein Y is methylenethe appropriate Formula V compound is combined with the appropriateprotected 4-halocrotonic acid, such as alkyl 4-halocrotonate, in thepresence of a base such as potassium carbonate in an aprotic solventsuch as dimethylformamide at a temperature of about 10° C. to about 50°C., typically ambient, for about 12 hours to about 72 hours.

The desired Formula V compound wherein R₁, R₂, R₃, R₄ and R₉ are asdescribed above may be prepared from the appropriate correspondingFormula VI compound by hydroxyalkylation (a modified Friedel-Craftsreaction).

Generally, the Formula VI compound is combined with a Lewis acid such asboron trichloride in a reaction-inert solvent such as benzene or tolueneat a temperature of about ambient to about reflux for about 1 to about 6hours under a nitrogen atmosphere to form an intermediate complex. Theresulting complex is combined with the appropriately substitutednaphthaldehyde in a reaction-inert solvent such as benzene in thepresence of an amine base such as triethylamine at a temperature ofabout 0° C. to about 40° C., typically ambient, for about 30 minutes toabout 18 hours followed by acid cleavage of the boron moiety.

Alternatively, a Formula V compound, wherein R₁ is 4-trifluoromethyl andR₄ is neopentyl, may be prepared by treating a Formula VI compound,wherein R₁ is 4-trifluoromethyl and R₄ is pivaloyl, with excess strongbase, preferably 2.5 equivalents of n-butyllithium, in an anhydrousethereal solvent, preferably tetrahydrofuran, at a temperature of aboutambient to about 50° C. for about 1 hour to about 3 hours and reactingthe resulting dianion with the appropriate naphthaldehyde. The resulting2-(alpha-hydroxymethyinaphthalene) Formula V compound, wherein R₄ ispivaloyl, is converted to the Formula V compound, wherein R₁ is4-trifluoromethyl and R₄ is neopentyl, by reducing the pivalamidefunctionality with a reducing agent such as lithium aluminum hydride orborane, preferably a borane-tetrahydrofuran complex, in an etherealsolvent such as tetrahydrofuran at an elevated temperature, typicallyreflux. Alternatively, the Formula V compounds wherein R₁ is4-trifluoromethyl and R₄ is alkyl, including neopentyl, may be preparedby treating the Formula VI compound, wherein R₁ is 4-trifluoromethyl andR₄ is t-butoxycarbonyl, with an excess of t-butyllithium, preferably 2.4equivalents, at a temperature of about -50° C. to about 0° C. in anethereal solvent such as anhydrous tetrahydrofuran for about 2 hours toabout 4 hours and coupling the resulting dianion with the appropriatenaphthaldehyde. The resulting 2-(alpha-hydroxymethylnaphthalene) FormulaV compound, wherein R₁ is 4trifluoromethyl and R₄ is t-butoxycarbonyl,is treated with acid and thereby converted to the Formula V compound,wherein R₁ is 4-trifluoromethyl and R₄ is H. This compound istransformed to the Formula V compound, wherein R₁ is 4-trifluoromethyland R₄ is alkyl, by reductive amination under conditions similar to thatfor the preparation of the Formula VI compounds.

The desired Formula VI compound wherein R₁, R₂ and R₄ are as describedabove may be prepared from the appropriate corresponding aniline byreductive amination.

Generally, the aniline is reacted with the appropriate alkylaldehyde ina protic acidic solvent such as concentrated acetic acid at atemperature of about 10° C. to about 50° C., preferably ambient, forabout 30 minutes to about four hours followed by reduction using forexample sodium borohydride at a temperature of about 0° C. to about 20°C. for about 15 minutes to about four hours.

Alternatively, the aniline is reacted with the appropriate alkylaldehydein an aprotic solvent such as 1,2-dichloroethane in the presence of anacid such as acetic acid at a temperature of about 15° C. to about 40°C., preferably ambient temperature, for a period of about 1 to about 20hours followed by reduction using for example sodiumtriacetoxyborohydride at about -20° C. to about ambient temperature fora period of about 1 to about 20 hours.

According to Reaction Scheme II the desired Formula VII compoundswherein R₁, R₂, R₃, R₄ and R₉ are as described above, X is thio, Y iscarbonyl or methylene and Z is a substituted amide may be prepared byacylating the appropriate amine with the corresponding Formula VIII orIX compound wherein Z is carboxyl. Generally this reaction may beperformed as describe above for the Formula II compounds.

The desired Formula VIII compounds wherein R₁, R₂, R₃, R₄ and R₉ are asdescribed above, X is thio, Y is methylene may be prepared from theappropriate corresponding Formula IX compound where Y is carbonyl by asequential reduction/oxidation procedure.

Generally the Formula IX compound is fully reduced using for example aborane-methyl sulfide complex in a reaction-inert solvent such astetrahydrofuran at a temperature of about 20° C. to about 80° C.,preferably at reflux, for about 1 hour to about 6 hours. The resultingalcohol is then oxidized to the Formula VIII compound using for examplea two step procedure involving first a Swern oxidation followed byoxidation with buffered sodium chlorite in acetonitrile and aqueoushydrogen peroxide at a temperature of about -10° C. to about 25° C. forabout 30 minutes to about 4 hours. Or alternatively, the alcohol isdirectly oxidized to the acid using t-butyl hydroperoxide and cetyltrimethyl ammonium sulfate in an aqueous mixture at pH>13.

The desired Formula IX compound wherein R₁, R₂, R₃, R₄ and R₉ are asdescribed above, may be prepared from the appropriate correspondingFormula X compound by alkylation followed by epimerization and finallyhydrolysis.

Generally, the Formula X compound is combined with a base such aslithium diisopropylamide in a reaction-inert solvent such ascyclohexane/tetrahydrofuran at a temperature of about -100° C. to about-20° C. under nitrogen for about 30 minutes to about 3 hours followed byaddition of a suitable alkyl haloacetate such as t-butyl bromoacetateand mixing for about 2 to about 24 hours at a temperature of about 10°C. to about 40° C., preferably ambient. The alkylated product isepimerized to exclusively the trans isomers using a base like potassiumcarbonate in an alcoholic solvent like methanol for 1 hour to 6 hours ata temperature of about 40° C. to about 80° C., preferably at 60° C. Theresulting t-butyl ester may be hydrolyzed by treatment with an acid suchas trifluoroacetic acid in a reaction-inert solvent such asdichloromethane.

The desired Formula X compound wherein R₁, R₂, R₃, R₄ and R₉ are asdescribed above, may be prepared from the appropriate correspondingFormula XI compound by coupling under carbodiimide conditions.

Generally, the Formula XI compound is combined with a suitablecarbodiimide such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride in a reaction-inert solvent such as dichloromethane at atemperature of about 10° C. to about 50° C., conveniently at ambienttemperature, for about 5 hours to about 24 hours.

The desired Formula XI compound wherein R₁, R₂, R₃, R₄ and R₉ are asdescribed above, may be prepared from the appropriate correspondingFormula V compound by a solvolytic displacement reaction.

Generally, the Formula V compound may be combined with mercaptoaceticacid under aqueous acidic conditions at a temperature of about 60° C. toabout 120° C., conveniently at reflux, for about 2 to about 6 hours.

Alternatively, the desired Formula IX compounds wherein R₁, R₂, R₃, R₄,and R₉ are as described above may be prepared from the appropriatecorresponding Formula V compound by a solvolytic displacement reactionwith cyclization to the lactam followed by epimerization.

Generally, the Formula V compound and mercaptosuccinic acid are combinedin a carboxylic acid solvent such as propionic acid and heated to about100° C. to about 140° C. for about 12 to 72 hours with a means to removewater such as a nitrogen sweep across the head space of the reactionvessel. The cyclized product is epimerized to the trans isomers bytreatment in an inert solvent such as tetrahydrofuran with a base suchas a metal alkoxide base in the corresponding alcohol solvent,preferably sodium methoxide in methanol, at about ambient temperature toreflux temperature for a period of about 1 to about 24 hours.

The starting materials and reagents for the above described reactionschemes (e.g., 4-haloaniline, 1-naphthaldehyde, furmaric acid monoethylester, amino acid esters, prodrug residues, protected forms) are readilyavailable or can be easily synthesized by those skilled in the art usingconventional methods of organic synthesis. Some of the preparationmethods described herein will require protection of remote functionality(i.e., carboxyl). The need for these protecting groups will varydepending on the nature of the remote functionality and the conditionsof the preparation methods. This need is readily determined by oneskilled in the art. For a general description of protecting groups(e.g., halo(C₁ -C₄)alkyl, (C₁ -C₄)alkoxymethyl, arylmethyl and tri(C₁-C₄)alkylsilyl) and their use, see T. W. Greene, Protective Groups inOrganic Synthesis, John Wiley & Sons, New York, 1991.

The compounds of Formula I have asymmetric carbon atoms and thereforeare enantiomers or diastereomers. Diasteromeric mixtures can beseparated into their individual diastereomers on the basis of theirphysical chemical differences by methods known per se., for example, bychromatography and/or fractional crystallization. Enantiomers (e.g., ofFormula III, VII or IX) can be separated by converting the enantiomericmixture into a diasteromeric mixture (e.g., ester or salt) by reactionwith an appropriate optically active compound (e.g., alcohol or amine),separating the diastereomers and converting (e.g., hydrolyzing oracidifying) the individual diastereomers to the corresponding pureenantiomers. All such isomers, including diastereomers and enantiomersare considered as part of this invention.

Some of the compounds of this invention, where for example Z contains anacid group, are acidic and they form a salt with a pharmaceuticallyacceptable cation. All such salts are within the scope of this inventionand they can be prepared by conventional methods. For example, they canbe prepared simply by contacting the acidic and basic entities, usuallyin a stoichiometric ratio, in either an aqueous, non-aqueous orpartially aqueous medium, as appropriate. The salts are recovered eitherby filtration, by precipitation with a non-solvent followed byfiltration, by evaporation of the solvent, or, in the case of aqueoussolutions, by lyophilization, as appropriate.

Some of the compounds of this invention where, for example Y ismethylene or Z contains an amine group are basic, and they form a saltwith a pharmaceutically acceptable anion. All such salts are within thescope of this invention and they can be prepared by conventionalmethods. For example, they can be prepared simply by contacting theacidic and basic entities, usually in a stoichiometric ratio, in eitheran aqueous, non-aqueous or partially aqueous medium, as appropriate. Thesalts are recovered either by filtration, by precipitation with anon-solvent followed by filtration, by evaporation of the solvent, or,in the case of aqueous solutions, by lyophilization, as appropriate.

In addition, when the compounds of this invention form hydrates orsolvates they are also within the scope of the invention.

The compounds of this invention are all adapted to therapeutic use asagents that lower plasma LDL cholesterol levels in mammals, particularlyhumans. Since the concentration of cholesterol in blood is closelyrelated to the development of cardiovascular, cerebral vascular orperipheral vascular disorders, these compounds, by virtue of theirhypocholesterolemic action, prevent, arrest and/or regressatherosclerosis.

The hypocholesterolemia activity of these compounds can be determined byassessing the effect of these compounds on the action of squalenesynthetase by measuring the overall conversion of 1-³ H!farnesylpyrophosphate to ³ H!squalene, essentially as previously described inMeth. Enzymol. 110, 359, 1985 using the anaerobic atmosphere generatingoxygen consumption system described in Analyt. Biochem. 203, 310, 1992,in comparison to known controls (e.g., zaragozic acid A).

Briefly, to a 3 μl volume of either DMSO (control) or DMSO containingcompound, are added 47 μl of Squalene Synthetase Cofactor/Substratesolution (SQS Cofactor/Substrate solution contains 50 mM K_(x) PO₄(pH=7.4), 5.0 mM MgCl₂, 411 μM NADP⁺, 3.4 mM glucose-6-phosphate, 20U/ml glucose-6-phosphate dehydrogenase, 15 mM NaF, 78.1 mM sodiumascorbate, 31.3 U/ml ascorbate oxidase, and 1.56 times the indicatedfinal concentrations of {³ H!FPP (sp. act. 380/pmol)) and 25 μl of PMEDbuffer (PMEB buffer contains 50 mM K_(x) PO₄ (pH 7.4), 5 mM MgCl₂, 1.0mM EDTA, 5.0 mM dithiothreitol) containing 1 mg/ml microsomal proteinFinal assay concentrations: 48 mM K_(x) PO₄ (pH 7.4), 4.8 mM MgCl₂, 0.33mM EDTA, 1.67 mM DTT, 258 μM NADP⁺, 2.1 mM glucose-6-phosphate, 0.95Uglucose-6-phosphate dehydrogenase, 9.5 mM NaF, 50 mM sodium ascorbate,1.5U ascorbate oxidase, 4% DMSO, and 5.1 μM ³ H!farnesyl pyrophosphate!.After incubation at 37° C. for 30 min, enzymatic reactions areterminated by sequential addition of 40 μl 10M NaOH, 40 μl EtOH, 10 μlof 2 mg/ml squalene in chloroform. After saponification (90 minutes, 37°C.), aliquots were applied to silica gel TLC and newly formed squaleneseparated from unreacted substrate by chromatography in toluene-ethylacetate (9:1). The squalene band is visualized with iodine vapors,removed, and immersed in Aqualsol-2 liquid scintillation fluid. Squalenesynthetase activity is expressed as pmoles of squalene formed fromfarnesyl pyrophosphate per min of incubation at 37° C. per mg microsomalprotein, based on the stoichiometry of the reaction whereby two moles of³ H!farnesyl pyrophosphate react to form one mole of ³ H!squalene andhalf of the radiolabel is lost from the C-1 position of the prenylating³ H!farnesyl pyrophosphate due to 1-pro-S hydrogen release. Rat hepaticmicrosomes are used as the source of squalene synthetase activity asdescribed by Harwood et al (J. Lipid Res. 34, 377, 1993). Briefly,hepatic tissues are rinsed in phosphate buffered saline and immediatelyhomogenized at 4° C. in PMED buffer, using a Dounce tissue homogenizer.Homogenates are centrifuged at 10,000×g for 20 min at 4° C. and theresultant supernatants are centrifuged at 178,000×g for 90 min at 4° C.Microsomal pellets were resuspended in PMED buffer by a Potter-Elvehjempestle and stored frozen in liquid N₂ until use. For such preparations,there is no notable loss in enzyme activity within 3 months.

The hypercholesterolemic treating activity of these compounds may bedemonstrated by methods based on standard procedures. For example, thein vivo activity of these compounds in inhibiting cholesterolbiosynthesis may be determined by the procedure of Hughes et. al. 1977J. Biol Chem. 252: 548.

Activity of these compounds can be determined by the amount ofhypocholesterolemic agent that reduces hepatic cholesterol biosynthesis,relative to control, in male CD1 mice. Male CD1 mice are maintained on acholesterol-free diet in a 12 hr light/12 hr dark cycle. At mid lightcycle animals are administered a 0.5 mL oral bolus of saline containing0.25% methyl cellulose, 0.6% Tween 80 and 10% ethanol (control animals)or an oral bolus that contained in addition the desired concentration ofcompound to be tested. One hour following bolus administration theanimals receive an intraperitoneal injection (0.15 ml) of ¹⁴C!-mevalonolactone dissolved in water (0.5 uCi/animal). One hourfollowing the injection of radioactivity animals are sacrificed, liversexcised, saponified (saponified (2.5 M KOH, 2h) 60° C.) and extractedwith petroleum ether and ethanol. After saponification, theradioactivity is measured. Total hepatic radioactivity is calculatedbased on measured liver weights. The degree of cholesterol biosynthesisinhibition is expressed as a percentage of the total radioactivity intreated vs control animals. The above assay carried out with a range ofdoses of test compounds allow the determination of an approximate ED₅₀value for the in vivo reduction of hepatic cholesterol biosynthesis.

The hypercholesterolemic treating activity of these compounds may alsobe demonstrated by determining the amount of agent required to reducecholesterol levels, for example LDL cholesterol levels, in the plasma ofcertain mammals, for example marmosets that possess a plasma lipoproteinprofile similar to that of humans (Crook et al. Arteriosclerosis 10,625, 1990). Cholesterol synthesis inhibitors, for example HMG-CoAreductase inhibitors and the squalene synthetase inhibitor zaragozicacid A, lower plasma cholesterol concentrations in this species (Baxter,et al., J. Biol. Chem. 267, 11705, 1992). Adult marmosets are assignedto treatment groups so that each group has a similar mean ±SD for totalplasma cholesterol concentration. After group assignment, marmosets aredosed daily with compound as a dietary admix or by intragastricintubation for from one to eight weeks. Control marmosets receive onlythe dosing vehicle. Plasma total, LDL and HDL cholesterol values can bedetermined at any point during the study by obtaining blood from anantecubital vein and by separating plasma lipoproteins into theirindividual subclasses by density gradient centrifugation, and bymeasuring cholesterol concentration as previously described (Crook, etal., Arteriosclerosis 10, 625, 1990).

Anti-atherosclerosis effects of the compounds can be determined by theamount of agent required to reduce the lipid deposition in the rabbitaorta. Male New Zealand White rabbits are fed a diet containing 0.4%cholesterol and 5% peanut oil for 4 days (meal-fed once per day).Rabbits are bled from the marginal ear vein and total plasma cholesterolvalues are determined from these samples. The rabbits are then assignedto treatment groups so that each group has a similar mean ±s.d. fortotal plasma cholesterol concentration. After group assignment, rabbitsare dosed daily with compound given as a dietary admix or on a smallpiece of gelatin based confection. Control rabbits receive only thedosing vehicle be it the food or the gelatin confection. Thecholesterol/peanut oil diet is continued along with the compoundadministration throughout the study. Plasma cholesterol values can bedetermined at any point during the study by obtaining blood from themarginal ear vein. After 5 months, the rabbits are sacrificed and theaortae are removed from the thoracic arch to the branch of the iliacarteries. The aortae are cleaned of adventitia, opened longitudinallyand then stained with Sudan IV as described by Holman et al. (Lab.Invest. 1958, 7, 4247). The percent of the surface area stained isquantitated by densitometry using an Optimas Image Analyzing System(Image Processing Systems). Reduced lipid deposition is indicated by areduction in the percent surface area stained in the drug group incomparison with the control rabbits.

Administration of the compounds of this invention can be via any methodwhich delivers the squalene synthetase inhibitor to the intestine andthe liver. These methods include oral routes, parenteral, intraduodenalroutes etc.

Thus, for example, in one mode of administration a squalene synthetaseinhibitor of this invention may be administered once at night prior tosleep. Alternatively the compounds may be administered twice or threetimes daily with or without meals. In any event the amount and timing ofcompound(s) administered will, of course, be dependent on the subjectbeing treated, on the severity of the affliction, on the manner ofadministration and on the judgment of the prescribing physician. Thus,because of patient to patient variability, the dosages given below are aguideline and the physician may titrate doses of the drug to achieve theplasma cholesterol lowering that he/she considers appropriate for thepatient. In considering the degree of hypocholesterolemic activitydesired, the physician must balance a variety of factors such asstarting cholesterol level, other cardiovascular risk factors, presenceof preexisting disease, and age of the patient and his/her motivation.Those skilled in the art will know of the National Cholesterol Educationprogram guidelines for treatment of hypercholesterolemia (Circulation1991; 83:2154) In general an effective dosage for the squalenesynthetase inhibitors described above is in the range of 0.0005 to 50mg/kg/day, preferably 0.001 to 25 mg/kg/day, most preferably 0.005 to 5mg/kg/day. For an average 70 kg human, this would amount to 0.000035 to3.5 g/day, preferably 0.00007 to 1.75 g/day, most preferably 0.00035 to0.35 g/day.

The present invention compounds also demonstrate broad spectrumantifungal activity as determined by broth or agar dilution methods.

In case of administering the compound of the present invention for thetherapy of fungus infections, generally from 0.0005 to 100 mg/kg/dayshould be employed as a unit dosage in an antifungal treatment.

The antifungal activity of the compound of this invention may bedetermined with a bioassay that utilizes Crypococcus bhutenensis FD23971. A ten-day-old slant of C. bhutenensis is washed with 10 mL ofsterile water, and 300 μl of the suspension is mixed with an assaymedium consisting of 0.67% of yeast nitrogen based medium (DIFCO) and0.5% of glucose. 150 mL of the warm medium is poured onto a sterile,polystyrene bioassay plate (245×245×20 mm) and is left to solidify. Thesolid medium is bored into well-separated wells with a size #2 corkbore, and a suitable solution of the compound to be tested is spottedinto the wells. The plates are incubated at 28° C. for 2 to 3 days andthe zone of inhibition is measured according to standard proceduresagainst controls.

As an antifungal treatment the compounds of this invention areadministered to mammals (e.g., humans) by conventional methods.

Since the compounds of this invention are cholesterol biosynthesisinhibitors they can also lower the levels of Apolipoprotein E isoform 4circulating in the bloodstream Apolipoprotein E isoform 4 that is madein the brain also circulates through the central nervous system and ispresent in the cerebrospinal fluid. Compounds of this invention areuseful for the treatment of Alzheimer's disease.

Apolipoprotein E isoform 4 ("ApoE isoform 4") is an apolipoprotein whichis the gene product of the apolipoprotein E Type 4 allele and is carriedin the bloodstream on lipoproteins including LDL. Possession of one ortwo copies of the apolipoprotein E type 4 allele has been linked to agreatly increased risk of developing Alzheimers disease. In the liver,low density lipoprotein receptors (LDL receptors) are responsible forabsorbing and taking up from the bloodstream various lipoproteinsincluding some of those containing ApoE isoform 4. LDL receptors areregulated by gene repressors derived from cholesterol that suppress thetranscription of the LDL-receptor. Inhibition of cholesterolbiosynthesis reduces the presence of these cholesterol-derived LDL generepressors. This relieves the suppression of the production of the LDLreceptor, leading to production of additional LDL receptors in theliver, which in turn, remove additional amounts of lipoproteinsincluding ApoE Type 4 containing lipoproteins from the bloodstream.

The Alzheimer's disease treating activity of these compounds can bedetermined by assessing the effect of these compounds on the action ofsqualene synthetase by measuring the overall conversion of 1-³ H!famesylpyrophosphate to ³ H!squalene, essentially as previously described inMeth. Enzymol. 110, 359, 1985 using the anaerobic atmosphere generatingoxygen consumption system described in Analyt. Biochem. 203, 310, 1992,in comparison to known controls (e.g., zaragozic acid A). This assay isdescribed more fully above.

The Alzheimer's disease treating activity of these compounds may also bedemonstrated by determining the amount of agent required to reducecholesterol levels, for example LDL cholesterol levels, in the plasma ofcertain mammals, for example marmosets that possess a plasma lipoproteinprofile similar to that of humans (Crook et al. Arteriosclerosis 10,625, 1990). Cholesterol synthesis inhibitors, for example HMG-CoAreductase inhibitors and the squalene synthetase inhibitor zaragozicacid A, lower plasma cholesterol concentrations in this species (Baxter,et al., J. Biol. Chem. 267, 11705, 1992). This assay is described morefully above.

The compounds of this invention may be administered in conventionalmethods for the treatment of Alzheimer's disease. In general aneffective dosage for the squalene synthetase inhibitors of thisinvention for the treatment of Alzheimer's disease is in the range foradults of from about 1 mg to 1000 mg (preferably 5 to 100 mg,) which maybe given in a single dose or in two to four divided doses. Higher dosesmay be favorably employed as required.

Since the compounds of this invention are squalene synthesis inhibitorsthey are effective for the treatment of acne vulgaris. Squalene is amajor component of sebum, comprising about 12% of sebum in adults. Theseverity of acne vulgaris correlates directly with the sebum secretionrate and several compounds which decrease sebum secretion rate have beenshown to improve acne. By inhibiting squalene the compounds of thisinvention can decrease the sebum secretion rate and thereby improveacne.

The concentration of squalene in sebum increases four-fold after pubertyand It is believed that this increase in squalene concentration alone orin concert with other changes in sebum composition or sebum secretionrate facilitate the development of acne. The compounds of this inventionare useful in preventing or mollifying acne by reducing the percentageand total amount of squalene in sebum.

In addition to reducing squalene levels in sebum, by limiting theproduction of epoxides, the sebum may become less inflammatory (throughmetabolic action of the ever-present P. acnes). The compounds of thisinvenetion may therefor provide a dual effect to combat acne and thusconstitute a new, better treatment for acne than current keratolytic andanti-androgen therapies.

The anti-acne activity of the compounds of this invention may bedemonstrated by testing the in vitro effects of the compounds in humansebaceous gland culture using conditions similar to those described inFEBS Letters 200(1), 173-176 (1986) and J. Cell Science 95, 125-136(1990). Thus, the human sebaceous gland culture may be incubated withthe test compound and subsequent sebum production and qualitativechanges of sebum composition measured over a short period of time andcompared with controls and other actives.

For the treatment of acne the compounds of this invention may beadministered by conventional methods. For the treatment of acne eachdosage unit will preferably contain 0.001 mg to 1000 mg, advantageously0.01 mg to 400 mg, of active ingredient. The daily dosage as employedfor adult human treatment will preferably range from 0.001 mg to 5000 mgof active ingredient, most preferably from 0.01 mg to 2000 mg which maybe administered in 1 to 4 daily doses, for example, depending on theroute of administration and on the condition of the patient.

The compounds of this invention may also be used in conjunction withother pharmaceutical agaents. For example, they may be used incombination with fibrates, niacins, ion-exchange resins, antioxidants,ACAT inhibitors and bile acid sequestrants as a measns of loweringplasma cholesterol and as a means of treating atherosclerosis.Alternatively, they may be used in conjunction with another anti-acneagent (e.g. a topical antibiotic). In combination therapy treatment,both the squalene synthetase inhibitors of this invention and the otherdrug therapies are administered to mammals (e.g., humans) byconventional methods.

The compounds can be administered individually or together in anyconventional oral or parenteral dosage form such as a capsule, tablet,powder, cachet, suspension or solution. For oral administration, whichis preferred, a pharmaceutical composition can take the form ofsolutions, suspensions, tablets, pills, capsules, powders, and the like.

Depending on the intended mode of administration, the pharmaceuticalcompositions may be in the form of solid, semi-solid or liquid dosageforms, such as, for example, tablets, pills, capsules, powders, liquids,suspensions, or the like, preferably in unit dosage forms suitable forsingle administration of precise dosages. The pharmaceuticalcompositions will include a conventional pharmaceutical carrier orexcipient and a compound(s) according to the invention as an activeingredient. In addition, it may include other medicinal orpharmaceutical agents, carriers, adjuvants, etc.

Pharmaceutical compositions according to the invention may contain0.1%-95% of the compound(s) of this invention, preferably 1%-70%. In anyevent, the composition or formulation to be administered will contain aquantity of a compound(s) according to the invention in an amounteffective to treat the signs of the subject being treated, i.e.,hypercholesterolemia, atherosclerosis, Alzheimer's disease or fungalinfection.

For solid pharmaceutical compositions, conventional non-toxic solidcarriers include, for example, pharmaceutical grades of mannitol,lactose, starch, magnesium stearate, sodium saccharin, talcum,cellulose, glucose, sucrose, magnesium carbonate, and the like.

Liquid pharmaceutically administrable compositions can be prepared bydissolving or dispersing, or otherwise preparing a compound(s) accordingto this invention and mixing it optionally with a pharmaceuticaladjuvant in a carrier, such as, for example, water, saline, aqueousdextrose, glycerol, ethanol, and the like, to thereby form a solution orsuspension.

Methods of preparing various pharmaceutical compositions with a certainamount of active ingredient are known, or will be apparent in light ofthis disclosure, to those skilled in this art. For examples, seeRemington's Pharmaceutical Sciences., Mack Publishing Company, Easter,Pa., 15th Edition (1975).

EXAMPLE 1 Ethyl ester oftrans-7-chloro-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-aceticacid EXAMPLE 1A (4-Chloro-phenyl)-(neopentyl)-amine

Pivalaldehyde (20.4 g, 236 mmol, 25.6 mL) was added to a solution of4-chloroaniline (30.2 g, 236 mmol) in concentrated acetic acid (475 mL)at ambient temperature. After 1.5 hour, the reaction mixture was cooledto 0° C. and sodium borohydride (11.7 g, 307 mmol) was added portionwiseover 15 minutes After stirring for 1 hour, the resulting mixture wasdiluted with water and extracted with ethyl acetate (3×). The combinedorganics were washed successively with water (3×), aqueous 2N sodiumhydroxide (2×), saturated aqueous sodium bicarbonate, and saturatedaqueous sodium chloride, dried over anhydrous sodium sulfate, filtered,and concentrated under reduced pressure to give 47.2 g (99%) of thetitle compound as an off-white solid which was taken on crude to thenext step.

¹ H NMR (250 MHz, CDCl₃) δ 7.10 (d, 2H), 6.53 (d, 2H), 3.65 (br s, 1 H),2.85 (s, 2H), 0.98 (s, 9H).

EXAMPLE 1B (5-Chloro-2-neopentylamino-phenyl)-naphthalen-1-yl-methanol

A solution of (4-chloro-phenyl)-(neopentyl)-amine (6.58 g, 33.3 mmol) inbenzene (15 mL) was added to a solution of boron trichloride (1.0 M inxylenes; 36.6 mL, 36.6 mmol) in benzene (40 mL) at 0° C. under anitrogen atmosphere. Once the addition was complete, the resultingmixture was heated at reflux for 2 hours and then recooled to 0° C. Asolution of 1-naphthaldehyde (5.72 g, 36.6 mmol, 5.0 mL), triethylamine(6.74 g, 66.6 mmol, 9.3 mL) and benzene (15 mL) was then added and theresulting mixture stirred 1 hour before diluting with ethyl acetate andaqueous 2N hydrochloric acid. The resulting mixture was shakenvigorously, the aqueous layer alkalized with aqueous 5N sodiumhydroxide, and the layers separated. The aqueous layer was extractedwith ethyl acetate (2×). The organic layers were combined, dried overanhydrous sodium sulfate, filtered, concentrated under reduced pressure,and purified by flash column chromatography (5:1 hexanes/ethyl acetate)to produce 7.95 g (67%) of the title compound as a pale yellow solid.

MS (PCl): 354.

¹ H NMR (250 MHz, CDCl₃) δ 8.00 (m, 1H), 7.89 (m, 2H), 7.51 (m, 4H),7.15 (dd, 1H), 6.93 (d, 1H), 6.64 (d, 1H), 6.51 (s, 1H), 4.42 (br s,1H), 2.83 (s, 2H), 2.38 (br s, 1H), 0.84 (s, 9H).

EXAMPLE 1C 3-4-Chloro-2-(hydroxy-naphthalen-1-yl-methyl)-phenyl!-neopentyl-carbamoyl!-acrylicacid ethyl ester

Fumaric chloride monoethyl ester (5.48 g, 33.7 mmol) was added to amixture of (5-chloro-2-neopentylamino-phenyl)-naphthalen-1-yl-methanol(7.95 g, 22.5 mmol) and sodium bicarbonate (3.77 g, 45.0 mmol) inmethylene chloride (45 mL). After stirring 18 hours at ambienttemperature, the reaction mixture was diluted with methylene chloride,washed with water (2×) and saturated aqueous sodium chloride, dried overanhydrous sodium sulfate, filtered, concentrated under reduced pressure,and purified by flash column chromatography (5:1 hexanes/ethyl acetate)to produce 10.12 g (94%) of the title compound as a pale yellow foam.

MS (PCl): 480.

¹ H NMR (250 MHz, CDCl₃, major rotamer) δ 7.85-7.69 (m, 4H), 7.58-7.15(m, 6H), 6.51 (d, 1H), 6.18 (d, 2H), 4.44 (d, 1H), 4.06 (qd, 2H), 3.20(d, 1H), 2.58 (d, 1H), 1.21 (t, 3H), 0.92 (s, 9H).

EXAMPLE 1D Ethyl ester oftrans-7-chloro-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-aceticacid

Potassium carbonate (5.82 g, 42.2 mmol) was added to a solution of 3-4-chloro-2-(hydroxy-naphthalen-1-yl-methyl)-phenyl!-neopentyl-carbamoyl!-acrylicacid ethyl ester (10.1 g, 21.1 mmol) in ethanol (60 mL). The resultingmixture was stirred at ambient temperature for 12 hours and concentratedunder reduced pressure. The resulting residue was taken up in ether,washed with water (2×) and saturated aqueous sodium chloride, dried overanhydrous sodium sulfate, filtered, concentrated under reduced pressure,and purified by flash column chromatography (5:1 hexanes/ethyl acetate)to produce 8.75 g (86%) of the title compound as a white solid.

MS (PCl): 481 (M+H⁺).

¹ H NMR (250 MHz, CDCl₃) δ 7.91 (d, 2H), 7.84 (d, 1H), 7.59 (t, 1H),7.51-7.30 (m, 5H), 6.63 (s, 1H), 6.53 (d, 1H), 4.56 (m, 2H), 4.15 (qd,2H), 3.48 (d, 1H), 3.09 (dd, 1H), 2.86 (dd, 1H), 1.26 (t, 3H), 1.04 (s,9H).

The title compounds of Examples 2-6 were prepared according toprocedures analogous to those described in Example 1.

EXAMPLE 2 Ethyl ester oftrans-7.8-methylenedioxy-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-aceticacid

87% yield.

MS (PCl): 491 (M+H⁺).

¹ H NMR (250 MHz, CDCl₃) δ 7.86 (m, 3H), 7.55 (m, 2H), 7.44 (m, 1H),7.32 (td, 1H), 6.93 (s, 1H), 6.58 (s, 1H), 5.97 (s, 1H), 5.87 (d, 2H),4.57 (m, 2H), 4.15 (m, 2H), 3.37 (d, 1H), 3.08 (dd, 1H), 2.86 (dd, 1H),1.26 (t, 3H), 1.07 (s, 9H).

EXAMPLE 3 Ethyl ester oftrans-7-chloro-5-(1-bromonaphthalen-2-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-aceticacid

90% yield.

MS (PCl): 560 (M+H⁺).

¹ H NMR (250 MHz, CDCl₃) δ 8.30 (m, 1H), 7.88 (m, 3H), 7.62 (m, 2H),7.37 (s, 2H), 6.54 (s, 1H), 6.52 (s, 1H), 4.54 (m, 2H), 4.16 (m, 2H),3.44 (d, 1H), 3.05 (dd, 1H), 2.84 (dd, 1H), 1.26 (t, 3H), 1.01 (s, 9H).

EXAMPLE 4 Ethyl ester oftrans-7-chloro-5-(4-methoxynaphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-aceticacid

67% yield.

MS (PCl): 510.

¹ H NMR (300 MHz, CDCl₃) δ 8.36 (m, 1H), 7.73 (d, 1H), 7.40 (m, 5H),6.91 (d, 1H), 6.60 (d, 1H), 6.54 (s, 1H), 4.46 (m, 2H), 4.15 (qd, 2H),4.06 (s, 3H), 3.48 (d, 1H), 3.09 (dd, 1H), 2.85 (dd, 1H), 1.26 (t, 3H),1.04 (s, 9H).

EXAMPLE 5 Ethyl ester oftrans-7-chloro-5-(4-hydroxynaphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-aceticacid

67% yield.

MS (PCl): 496.

¹ H NMR (300 MHz, CDCl₃) δ 8.33 (d, 1H), 7.62 (d, 1H), 7.38 (m, 5H),6.95 (d, 1H), 6.61 (s, 1H), 6.56 (s, 1H), 4.59 (m, 2H), 4.18 (m, 2H),3.45 (d, 1H), 1H), 2.89 (dd, 1H), 1.24 (t, 3H), 1.03 (s, 9H).

EXAMPLE 5A Ethyl ester oftrans-7-chloro-5-(4-dimethylamino-naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-aceticacid 81% yield.

MS (PCl): 523.

¹ H NMR (300 MHz, CDCl₃) δ 8.33 (d, 1H), 7.72 (d, 1H), 7.49-7.28 (m,5H), 7.16 (d, 1H), 6.63 (d, 1H), 6.55 (s, 1H), 4.56 (m, 2H), 4.15 (qd,2H), 3.47 (d, 1H), 3.08 (dd, 1H), 2.94 (s, 6H), 2.84 (d, 1H), 1.26 (t,3H), 1.03 (s, 9H).

EXAMPLE 5B Ethyl ester oftrans-7-methyl-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-41-benzoxazepine-3-acetic acid

88% yield.

MS (PCl): 461 (M+2H⁺).

.sup. 1H NMR (300 MHz, CDCl₃) δ 7.88 (m, 3H), 7.57 (m, 2H), 7.44 (td,1H), 7.31 (m, 2H), 7.16 (dd, 1H), 6.66 (s, 1H), 6.35 (d, 1H), 4.57 (m,2H), 4.15 (m, 2H), 3.52 (d, 1H), 3.08 (dd, 1H), 2.87 (dd, 1H), 2.03 (s,3H), 1.25 (t, 3H), 1.05 (s, 9H).

EXAMPLE 5C

Ethyl ester oftrans-7-chloro-5-(5-iodonaphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-aceticacid

86% yield.

MS (PCl): 606 (M+H⁺).

¹ H NMR (300 MHz, CDCl₃) δ 8.22 (d,1H), 8.08 (d,₁ H), 7.90 (d, 1H), 7.67(t,1H), 7.43 (m, 3H), 7.01 (t, 1H), 6.59 (s, 1H), 6.46 (d, 1H), 4.56 (m,2H), 4.15 (qd, 2H), 3.48 (d, 1H), 3.07 (dd, 1H), 2.85 (dd, 1H), 1.26 (t,3H), 1.02 (s, 9H).

EXAMPLE 5D Ethyl ester oftrans-7-methylthio-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-aceticacid

89% yield.

¹ H NMR (250 MHz, CDCl₃) δ 1.03 (s, 9H); 1.25 (t, 3H); 2.07 (s, 3H);2.85 (q, 1H); 3.08 (q, 1H); 3.48 (d, 1H); 4.14 (c, 2H); 4.53, 4.46,4.58, 4.61 (m, 2H); 6.4 (d, 1H); 6.63 (s, 1H); 7.23 (m, 1H); 7.33 (q,2H); 7.44 (t, 1H); 7.56 (c, 2H); 7.82 (d, 1H); 7.89 (d, 2H).

EXAMPLE 5E Ethyl ester of trans7-trifluoromethoxy-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-aceticacid

43% yield.

¹ H NMR (250 MHz, CDCl₃) δ 1.04 (s, 9H); 1.25 (t, 3H); 2.87 (q, 1H);3.11 (q, 1H); 3.5 (d, 1H); 4.15 (q, 2H); 4.55, 4.57, 4.59, 5.62 (m, 2H);6.38 (d, 1H); 6.63 (s, 1H); 7.23 (c, 1H); 7.31 (t, 1H); 7.46 (c, 3H);7.58 (t, 1H); 7.83 (d, 1H); 7.91 (d, 2H).

EXAMPLE 5F Ethyl ester oftrans-7,8-ethylenedioxy-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-aceticacid

18% yield.

¹ H NMR (250 MHz, CDCl₃) δ 1.05 (s, 9H); 1.26 (t, 3H); 2.85 (q, 1H);3.06 (q, 1H); 3.38 (d, 1H); 4.04, 4.25 (c, 6H); 4.52 (d, 1H); 4.59 (t,1H); 6.03 (s, 1H); 6.59 (s, 1H); 6.93 (s, 1H); 7.33 (t, 1H); 7.44 (t,1H); 7.56 (q, 2H); 7.8 (d, 1H); 7.87 (t, 2H).

EXAMPLE 5G Ethyl ester oftrans-7-trifluoromethyl-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-aceticacid

The title compound was prepared using the procedures described inExamples 1C and 1D.

73% yield.

¹ H NMR (250 MHz, CDCl₃) δ 1.05 (s, 9H); 1.26 (t, 3H); 2.87 (q, 1H);3.12 (q, 1H); 3.57 (d, 1H); 4.15 (m, 2H); 4.54 (q, 1H); 4.61 (d, 1H);6.67 (s, 1H); 6.83 (s, 1H); 7.31 (t, 1H); 7.44 (d, 2H); 7.61 (m, 3H);7.86 (d, 1H); 7.92 (d, 2H).

EXAMPLE 6 Ethyl ester oftrans-7,8-trimethylene-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-aceticacid

93% yield.

MS (PCl): 487 (M+H⁺).

¹ H NMR (300 MHz, CDCl₃) δ 7.87 (m, 3H), 7.63-7.29 (m, 5H), 6.69 (s,1H), 6.41 (s, 1H), 4.61 (m, 2H), 4.17 (m, 4H), 3.55 (d, 1H), 3.12 (dd,1H), 2.89 (m, 3H), 2.57 (m, 2H), 1.98 (m, 2H), 1.26 (t, 3H), 1.08 (s,9H).

EXAMPLE 6A Methyl ester oftrans-7-chloro-5-(4-methylamino-naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-aceticacid

α-Chloroethyl chloroformate (109 mg, 765 μmol, 83 μL) was added to asolution of the ethyl ester oftrans-7-chloro-5-(4-dimethylamino-naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-aceticacid (364 mg, 696 μmol) in 1,2- dichloroethane (3.5 mL) at 0° C. Theresulting mixture was heated at reflux. After 4 hours, additional ACE-Cl(380 μL) was added. ACE-Cl (750 μL) was added both the following morningand the morning after that. On the third morning, the brown reactionmixture was cooled to ambient temperature and concentrated under reducedpressure to a brown foam which was taken up in methanol (7 mL) andheated at reflux for 4 hours, cooled to ambient temperature,concentrated under reduced pressure, and purified by flash columnchromatography (2:1 hexanes/ethyl acetate with 1% triethylamine) to give279 mg (81%) of the title compound as a beige foam.

MS (PCl): 495.

¹ H NMR (300 MHz, CDCl₃) δ 7.86 (d, 1H), 7.68 (d, 1H), 7.50 (d, 1H),7.43-7.29 (m, 4H), 6.68 (m, 2H), 6.52 (s, 1H), 4.56 (m, 3H), 3.69 (s,3H), 3.46 (d, 1H), 3.10 (dd, 1H), 3.05 (s, 3H), 2.87 (dd, 1H), 1.03 (s,9H).

EXAMPLE 6B Ethyl ester oftrans-7-chloro-5-(4-phenylnaphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-aceticacid EXAMPLE 6B1 Ethyl ester oftrans-7-chloro-5-(4-trifluoromethanesulfonyloxy-naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-aceticacid

Trifluoromethanesulfonic anhydride (208 mg, 739 μmol, 120 μL) was addedto a solution of the ethyl ester oftrans-7-chloro-5-(4-hydroxynaphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-aceticacid (305 mg, 616 μmol), pyridine (195 mg, 2.46 mmol, 200 μL) andmethylene chloride (3 mL) at 0° C. The orange mixture was graduallywarmed to ambient temperature and stirred for 5 hours, diluted withether, washed with water (2×) and saturated aqueous sodium chloride,dried over anhydrous sodium sulfate, filtered, concentrated underreduced pressure, and purified by flash column chromatography (4:1hexanes/ethyl acetate) to afford 356 mg (92%) of the title compound as awhite solid.

¹ H NMR (250 MHz, CDCl₃) δ 8.17 (d, 1H), 7.90 (d, 1H), 7.67-7.36 (m,6H), 6.59 (s, 1H), 6.47 (s, 1H), 4.56 (m, 2H), 4.15 (qd, 2H), 3.49 (d,1H), 3.07 (dd, 1H), 2.85 (dd, 1H), 1.26 (t, 3H), 1.03 (s, 9H).

EXAMPLE 6B2 Ethyl ester oftrans-7-chloro-5-(4-phenylnaphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-aceticacid

To a solution of the ethyl ester oftrans-7-chloro-5-(4-trifluoromethanesulfonyloxy-naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-aceticacid (160 mg, 255 μmol) in toluene (2.5 mL) was successively addedtetrakis(triphenylphosphine)palladium(0) (9.4 mg, 8.2 μmol), 2M aqueoussodium carbonate (330 μL, 663 μmol), ethanol (1 mL), boronic acid (34.2mg, 280 μmol) and lithium chloride (21.6 mg, 510 μmol). The resultingorange solution was heated at 95° C. for 28 hours. The black solutionwas cooled to ambient temperature, diluted with ethyl acetate, washedwith 1N aqueous sodium hydroxide and saturated aqueous sodium chloride,dried over anhydrous sodium sulfate, filtered, concentrated underreduced pressure, and purified by flash column chromatography (4:1hexanes/ethyl acetate) to afford 137 mg (97%) of the title compound as awhite solid.

MS (PCl): 556.

¹ H NMR (300 MHz, CDCl₃) δ 8.01 (d, 1H), 7.94 (d, 1H), 7.63-7.34 (m,11H), (d, 1H), 6.71 (s, 1H), 4.63 (m, 2H), 4.18 (m, 2H), 3.53 (d, 1H),3.15 (dd, 1H), 2.92 (dd, 1H), 1.28 (t, 3H), 1.09 (s, 9H).

EXAMPLE 6C Ethyl ester oftrans-7-chloro-5-(4-carboxynaphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-aceticacid

A solution of the ethyl ester oftrans-7-chloro-5-(4-trifluoromethanesulfonyloxy-naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-aceticacid (152 mg, 242 μmol), potassium acetate (95 mg, 968 μmol), palladium(II) acetate (3 mg, 12 μmol), 1,1'-bis(diphenylphosphino)-ferrocene (27mg, 48 μmol) and dimethyl sulfoxide (3 mL) at 60° C. was purged withcarbon monoxide gas for 10 minutes and then maintained under a carbonmonoxide atmosphere for 3 hours. The reaction mixture was diluted withwater and extracted with ethyl acetate (3×). The combined organics weredried over anhydrous magnesium sulfate, filtered, concentrated underreduced pressure, and purified by prep plate (80:15:1chloroform/methanol/saturated ammonium hydroxide) to afford 99 mg (78%)of the title compound as a beige solid.

MS (PCl): 524.

¹ H NMR (250 MHz, CDCl₃) δ 9.17 (d, 1H), 8.51 (d, 1H), 7.98 (d, 1H),7.66-7.34 (m, 5H), 6.68 (s, 1H), 6.48 (d, 1H), 4.58 (m, 2H), 4.18 (qd,2H), 3.51 (d, 1H), 3.12 (dd, 1H), 2.90 (dd, 1H), 1.27 (t, 3H), 1.06 (s,9H).

EXAMPLE 6D Ethyl ester oftrans-7-chloro-5-(5-methylnaphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-aceticacid

Methyllithium (1.4 M in ether; 310 μL, 431 μmol) was added to a solutionof 1-aza-5-stannabicyclo 3.3.3!undecane chloride (127 mg, 431 μmol) andether (2 mL) at 0° C. The resulting mixture was stirred 30 minutes at 0°C. and then warmed to ambient temperature and stirred an additional 30minutes before concentrating under reduced pressure. The resultingresidue was taken up with the ethyl ester oftrans-7-chloro-5-(5-iodonaphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-aceticacid (218 mg, 359μmol), 1,1'-bis(diphenylphosphino)ferrocene!palladium(II) chloride complex with dichloromethane (1:1) (5.8 mg, 7.2 μmol) andtoluene (5 mL) and this mixture heated at reflux for 18 hours. Thereaction mixture was cooled to ambient temperature, diluted with ether,washed with 0.2 N aqueous hydrochloric acid, dried over anhydrous sodiumsulfate, concentrated under reduced pressure and purified by flashcolumn chromatography (5:1 hexanes/ethyl acetate) to provide 34 mg (19%)of the title compound as a white powder.

.sup. 1H NMR (250 MHz, CDCl₃) δ 8.09 (d, 1H), 7.86 (d, 1H), 7.62 (dd,1H), 7.48-7.17 (m, 5H), 6.63 (s, 1H), 6.52 (d, 1H), 4.56 (m, 2H), 4.16(qd, 1H), 3.48 (d, 1H), 3.09 (dd, 1H), 2.86 (dd, 1H), 2.74 (s, 3H), 1.26(t, 3H), 1.04 (s, 9H).

EXAMPLE 6E Ethyl ester oftrans-7-chloro-5-(5-phenylnaphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-aceticacid

Reaction performed in a manner similar to that described in Example 6B2using the ethyl ester oftrans-7-chloro-5-(5-iodonaphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-aceticacid as starting material under nonaqueous conditions using cesiumfluoride instead of lithium chloride and dimethylformamide as thesolvent.

quantitative yield.

¹ H NMR (300 MHz, CDCl₃) δ 7.96 (d, 1H), 7.85 (d, 1H), 7.55-7.36 (m,11H), (s, 1H), 6.62 (d, 1H), 4.58 (m, 2H), 4.15 (qd, 2H), 3.50 (d, 1H),3.10 (dd, 1H), 2.86 (dd, 1H), 1.26 (t, 3H), 1.06 (s, 9H).

EXAMPLE 6F Ethyl ester oftrans-7-chloro-5-(5-acetylnaphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-aceticacid

A mixture of the ethyl ester oftrans-7-chloro-5-(5-iodonaphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-aceticacid (204 mg,337 μmol), bis(triphenylphosphine)palladium (II) chloride(24 mg, 34μmol), (1-ethoxyvinyl)tributyltin (134 mg, 370 μmol, 125 μL)and toluene (2 mL) was heated at 100° C. for 48 hours under a nitrogenatmosphere and cooled to ambient temperature. Aqueous 2 N hydrochloricacid (2 mL) was added and the resulting mixture stirred 24 hours beforediluting with ether, washing with water, drying over anhydrous sodiumsulfate, concentrating under reduced pressure and purifying by flashcolumn chromatography (3:1 hexanes/ethyl acetate) to provide 163 mg(92%) of the title compound as a light brown foam.

MS (PCl): 522 (M+H⁺).

¹ H NMR (250 MHz, CDCl₃) δ 8.70 (d, 1H), 7.87 (m, 2H), 7.69 (m, 2H),7.37 (m, 3H), 6.60 (s, 1H), 6.48 (d, 1H), 4.56 (m, 2H), 4.14 (qd, 2H),3.48 (d, 1H), 3.07 (dd, 1H), 2.85 (dd, 1H), 2.76 (s, 3H), 1.25 (t, 3H),1.03 (s, 9H).

EXAMPLE 7 Ethyl ester oftrans-7,8-trimethylene-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid EXAMPLE 7A 4-4,5-Trimethylene-2-(hydroxy-naphthalen-1-yl-methyl)-phenyl!-(neopentyl)-amino!-but-2-enoicacid ethyl ester

Ethyl 4-bromocrotonate (203 mg, 1.05 mmol, 145 μL) was added to amixture of(4,5-trimethylene-2-neopentylamino-phenyl)-naphthalen-1-yl-methanol (344mg, 956 μmol; prepared as described in example 1) and potassiumcarbonate (159 mg, 1.15 mmol) in dimethylformamide (2 mL) at ambienttemperature. After stirring 20 hours, an additional amount of potassiumcarbonate (1.32 g, 956 mmol) and ethyl 4-bromocrotonate (922 mg, 4.78mmol, 658 μL) was added. After an additional 18 hours, the reactionmixture was diluted with ether, washed successively with water (2×) andsaturated aqueous sodium chloride, dried over anhydrous sodium sulfate,filtered, concentrated under reduced pressure, and purified by flashcolumn chromatography (5:1 hexanes/ethyl acetate) to produce 193 mg(43%) of the title compound.

EXAMPLE 7B Ethyl ester oftrans-7,8-trimethylene-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-4,1-benzoxazeline-3-aceticacid

4-4,5-Trimethylene-2-(hydroxy-naphthalen-1-yl-methyl)-phenyl!-(neopentyl)-amino!-but-2-enoicacid ethyl ester (193 mg, 408 μmol) was taken up in ethanol (3 mL) andpotassium carbonate (113 mg, 817 μmol) and stirred at ambienttemperature for 16 hours. The reaction mixture was diluted with ethylacetate, washed successively with water (2×) and saturated aqueoussodium chloride, dried over anhydrous sodium sulfate, filtered,concentrated under reduced pressure, and purified by flash columnchromatography (10:1 hexanes/ethyl acetate) to produce 127 mg (66%) ofthe title compound as an off-white solid.

MS (PCl): 472.

¹ H NMR (300 MHz, CDCl₃) δ 8.12 (d, 1H), 7.97 (m, 2H), 7.74.(d, 1H),7.50 (m, 3H), 7.00 (s, 1H), 6.33 (br s, 1H), 6.29 (s, 1H), 5.13 (dd,1H), 4.12 (q, 2H), 3.65 (d, 1H), 2.91 (m, 3H), 2.63 (t, 2H), 2.40 (t,2H), 2.31-1.87 (m, 4H), 1.25 (t, 3H), 1.09 (s, 9H).

EXAMPLE 8 Ethyl ester oftrans-7-chloro-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid

The title compound was prepared as described in example 7 except using10 equivalents of potassium carbonate and 5 equivalents of ethyl4-bromocrotonate initially and stirring at ambient temperature for 72hours.

27% yield for 2 steps.

MS (PCl): 466 (M+H⁺).

¹ H NMR (250 MHz, CDCl₃) δ 8.28 (d, 1H), 7.87 (d, 2H), 7.45 (m, 4H),7.04 (dd, 1H), 6.85 (d, 1H), 6.62 (d, 1H), 6.32 (s, 1H), 4.92 (dd, 1H),4.14 (q, 2H), 3.55 (d, 1H), 2.86 (d, 1H), 2.54 (m, 2H), 2.34 (m, 1H)2.11 (m, 1H), 1.25 (t, 3H), 1.12 (s, 9H).

EXAMPLE 9Trans-7-chloro-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-aceticacid

Potassium carbonate (5.03 g, 36.5 mmol) was added to a solution of theethyl ester of the title compound (18.75 g, 18.2 mmol) in methanol (60mL) and water (10 mL). The resulting mixture was heated at 60° C. for 18hours. After cooling to room temperature, the reaction mixture wasconcentrated and the resulting residue taken up in water, acidified withan aqueous solution of 1N hydrochloric acid and extracted with ethylacetate (3×). The combined organics were dried over anhydrous magnesiumsulfate, filtered, concentrated under reduced pressure, and purified byflash column chromatography (80:15:1 chloroform/methanol/saturatedammonium hydroxide) to produce a clear oil that was taken up in ethylacetate, washed with an aqueous solution of 1N hydrochloric acid, driedover anhydrous magnesium sulfate, filtered through a pad of Celite, andconcentrated under reduced pressure. The resulting solid was trituratedwith ether/hexanes to give 7.39 g (89%) of the title compound as a whitesolid.

MS (PCl): 453 (M+H⁺).

¹ H NMR (250 MHz, CDCl₃) δ 7.89 (m, 3H), 7.60 (t, 1H), 7.49-7.30 (m,5H), 6.63 (s, 1H), 6.54 (d, 1H), 4.58 (d, 1H), 4.51 (dd, 1H), 3.50 (d,1H), 3.14 (dd, 1H), 2.93 (dd, 1H), 1.05 (s, 9H).

The title compounds of Examples 10-1 6 were prepared according toprocedure analogous to those described in Example 9.

EXAMPLE 10Trans-7,8-methylenedioxy-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-aceticacid

66% yield.

MS (PCl): 463 (M+H⁺).

¹ H NMR (250 MHz, CDCl₃) δ 7.87 (m, 3H), 7.56 (m, 2H), 7.45 (t, 1H),7.32 (m, 1H), 6.93 (s, 1H), 6.58 (s, 1H), 5.98 (s, 1H), 5.91 (d, 2H),4.54 (m, 2H), 3.39 (d, 1H), 3.13 (dd, 1H), 2.93 (dd, 1H), 1.07 (s, 9H).

EXAMPLE 10B

Trans-7-methyl-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-aceticacid

81% yield.

MS (PCl): 433 (M+2H⁺).

¹ H NMR (300 MHz, CDCl₃) δ 7.78 (m, 3H), 7.56 (m, 2H), 7.44 (t, 1H),7.31 (m, 2H), 7.18 (m, 1H), 6.65 (s, 1H), 6.36 (d, 1H), 4.57 (d, 1H),4.51 (dd, 1H), 3.53 (d, 1H), 3.13 (dd, 1H), 2.93 (dd, 1H), 2.05 (s, 3H),1.05 (s, 9H).

EXAMPLE 10CTrans-7-methoxy-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-aceticacid

78% yield.

MS (PCl): 449 (M+2H⁺).

¹ H NMR (250 MHz, DMSO-d₆) δ 8.02 (d, 2H), 7.80 (d, 1H), 7.66 (m, 2H),7.45 (m, 3H), 7.05 (dd, 1H), 6.46 (s, 1H), 5.81 (d, 1H), 4.37 (m, 2H),3.67 (d, 1H), 3.47 (s, 3H), 2.85 (dd, 1H), 2.70 (dd, 1H), 0.96 (s, 9H).

EXAMPLE 10D

Trans-7-chloro-5-(5-iodonaphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-aceticacid

98% yield.

MS (PCl): 578 (M+H⁺).

¹ H NMR (300 MHz, CDCl₃) δ 8.21 (d,1H), 8.08 (d, 1H), 7.90 (d, 1H), 7.677.43 (m, 3H), 7.00 (t, 1H), 6.59 (s, 1H), 6.47 (s, 1H), 4.57 (d, 1H),4.50 (t 1H), 3.10 (dd, 1H), 2.95 (dd, 1H), 1.03 (s, 9H).

EXAMPLE 10ETrans-7-chloro-5-(5-methylnaphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-aceticacid

98% yield.

¹ H NMR (250 MHz, CDCl₃) δ 8.10 (d, 1H), 7.90 (d, 1H), 7.65 (t, 1H),7.50-7.20 (m, 5H), 6.65 (s, 1H), 6.55 (d, 1H), 4.50 (m, 2H), 3.50 (d,1H), 3.15 (dd, 1H), 2.90 (dd, 1H), 2.75 (s, 3H), 1.05 (s, 9H).

EXAMPLE 10FTrans-7-chloro-5-(5-phenylnaphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-aceticacid

86% yield.

MS (PCl): 528 (M+H⁺).

¹ H NMR (250 MHz, CDCl₃) δ 7.96 (d,1H), 7.86 (d, 1H), 7.56-7;33 (m,11H), 6.66 (s, 1H), 6.63 (d, 1H), 4.59 (d, 1H), 4.53 (dd, 1H), 3.51 (d,1H), 3.16 (dd, 1H), 2.94 (dd, 1H), 1.06 (s, 9H).

EXAMPLE 10GTrans-7-chloro-5-(5-acetylnaphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-aceticacid

53% yield.

MS (PCl): 494 (M+H⁺).

¹ H NMR (300 MHz, CDCl₃) δ 8.69 (d,1H), 7.87 (m, 2H), 7.70 (nm, 2H),7.44 (m, 3H), 6.60 (s, 1H), 6.49 (d,₁ H), 4.54 (m, 2H), 3.48 (d, 1H),3.14 (dd, 1H), 2.92 (dd, 1H), 2.75 (s, 3H), 1.03 (s, 9H).

EXAMPLE 11Trans-7-chloro-5-(1-bromonaphthalen-2-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-aceticacid

62% yield.

MS (PCl): 532 (M+H⁺).

¹ H NMR (250 MHz, CD₃ OD) δ 8.28 (m, 1H), 7.96 (m, 3H), 7.63 (m, 3H),7.44 (dd, 1H), 6.48 (s, 1H), 6.37 (d, 1H), 4.53 (m, 1H), 4.46 (d, 1H),3.62 (d, 1H), 2.76 (m, 2H), 1.00 (s, 9H).

EXAMPLE 12Trans-7-chloro-5-(4-methoxynaphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-aceticacid

96% yield.

MS (PCl): 482.

¹ H NMR (300 MHz, CDCl₃) δ 8.37 (d, 1H), 7.75 (d, 1H), 7.40 (m, 5H),6.92 (d, 1H), 6.61 (d, 1H), 6.56 (s, 1H), 4.55 (m, 2H), 4.04 (s, 3H),3.48 (d, 1H), 3.15 (dd, 1H), 2.93 (dd, 1H), 1.04 (s, 9H).

EXAMPLE 13Trans-7-chloro-5-(4-hydroxynaphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-aceticacid

20% yield.

¹ H NMR (300 MHz, CD₃ OD) δ 8.32 (d, 1H), 7.65 (d, 1H), 7.58 (d, 1H),7.39 (m, 4H), 6.93 (d, 1H), 6.46 (m, 2H), 4.48 (m, 2H), 3.63 (d, 1H),2.83 (m, 2H), 1.02 (s, 9H).

EXAMPLE 13ATrans-7-chloro-5-(4-dimethylamino-naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-aceticacid

92% yield.

MS (PCl): 495.

¹ H NMR (300 MHz, CDCl₃) δ 8.32 (d, 1H), 7.74 (d, 1H), 7.46-7.30 (m,5H), 7.17 (d, 1H), 6.64 (d, 1H), 6.55 (s, 1H), 4.57 (d, 1H), 4.50 (t,1H), 3.48 (d, 1H), 3.12 (dd, 1H), 2.94 (s, 6H), 2.89 (app d, 1H), 1.03(s, 9H).

EXAMPLE 13BTrans-7-chloro-5-(4-methylamino-naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-aceticacid

70% yield.

MS (PCl): 481.

¹ H NMR (300 MHz, CDCl₃) δ 7.86 (d, 1H), 7.70 (d, 1H), 7.51-7.29 (m,5H), 6.69 (m, 2H), 6.52 (s, 1H), 4.57 (d, 1H), 4.52 (t,₁ H), 3.47 (d,1H), 3.15 (dd, 1H), 3.05 (s, 3H), 2.92 (dd, 1H), 1.03 (s, 9H).

EXAMPLE 13CTrans-7-chloro-5-(4-phenylnaphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-aceticacid

64% yield.

MS (PCl): 528.

¹ H NMR (300 MHz, CD₃ OD, major conformer) δ 7.95 (m, 2H), 7.89 (s, 2H),7.69-7.32 (m, 9H), 6.62 (s, 1H), 6.49 (d, 1H), 4.49 (m, 2H), 3.70 (d,1H), 2.98 (s, 1H), 2.85 (s, 1H), 1.06 (s, 9H).

EXAMPLE 13DTrans-7-chloro-5-(4-carboxynaphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-aceticacid

84% yield.

MS (PCl): 496.

¹ H NMR (250 MHz, CD₃ OD) δ 8.99 (d, 1H), 8.29 (d, 1H), 7.95 (d, 1H),7.80 (d, 1H), 7.64-7.34 (m, 5H), 6.61 (s, ₁ H), 6.36 (d, 1H), 4.49 (m,2H), 3.65 (d, ₁ H), 3.01 (dd, 1H), 2.85 (dd, 1H), 1.04 (s, 9H).

EXAMPLE 13ETrans-7-chloro-5-(4-methoxycarbonylnaihthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-aceticacid

The ethyl ester of the title compound was prepared using a procedureanalogous to that described in example 6C using methanol (20equivalents) and triethylamine (2 equivalents) indimethylformamide-instead of dimethyl sulfoxide and potassium carbonate.Hydrolysis to the title compound was carried out using an analogousprocedure to that described in Example 9.

MS (PCl): 510.

EXAMPLE 14Trans-7,8-trimethylene-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-aceticacid

72% yield.

MS (PCl): 472.

¹ H NMR (300 MHz, CD₃ OD) δ 7.91 (dd, 2H), 7.85 (d, 1H), 7.50 (m, 4H),7.28 (m, 1H), 6.58 (s, 1H), 6.27 (s, 1H), 4.48 (m, 2H), 3.69 (d, 1H),2.96 (dd, 1H), 2.92 (t, 2H), 2.80 (dd, 1H), 2.55 (m, 2H), 1.98 (quintet,2H), 1.04 (s, 9H).

EXAMPLE 15Trans-7,8-trimethylene-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid

85% yield.

MS (PCl): 444.

¹ H NMR (300 MHz, CDCl₃) δ 8.37 (m, 1H), 7.86 (m, 2H), 7.49 (m, 4H),6.88 (s, 1H), 6.54 (s, 1H), 6.42 (s, 1H), 4.92 (s, 1H), 3.59 (d, 1H),2.87 (m, 3H), 2.62 (m, 4H), 2.42 (m, 1H), 2.12 (m, 1H), 1.97 (quintet,2H), 1.14 (s, 9H).

EXAMPLE 16Trans-7-chloro-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid

56% yield

MS (PCl): 438.

¹ H NMR (250 MHz, CDCl₃) δ 8.26 (d, 1H), 7.86 (d, 2H), 7.54-7.36 (m,4H), 7.04 (dd, 1H), 6.86 (d, 1H), 6.63 (d, 1H), 6.32 (s, 1H), 4.92 (dd,1H), 3.54 (d, 1H), 2.84 (d, 1H), 2.59 (m, 2H), 2.34 (m, 1H), 2.09 (m,1H), 1.11 (s, 9H).

EXAMPLE 17 Methyl ester of (-)-(R)-O-trans-7-chloro-5-(naphthalen-1-yl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!lacticacid and methyl ester of (+)-(R)-O-trans-7-chloro-5-(naphthalen-1-yl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!lacticacid

1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (309 mg,1.61 mmol) and 4-dimethylaminopyridine (59 mg, 484 μmol) were added to asolution oftrans-7-chloro-5-(naphthalen-1-yl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid (606 mg, 1.34 mmol) and methyl (R)-lactate (168 mg, 1.61 mmol) inmethylene chloride (15 mL) at ambient temperature. After stirring 5hours, the reaction mixture was diluted with ether, washed successivelywith aqueous solutions of 1N hydrochloric acid, saturated sodiumbicarbonate and saturated sodium chloride, dried over anhydrous sodiumsulfate, filtered, concentrated under reduced pressure, and purified byflash column chromatography (3:1 hexanes/ether, 200 mL silica).

As the less polar fraction, 268 mg of the methyl ester of (R)-O-(+)-trans-7-chloro-5-(naphthalen-1-yl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!lacticacid was isolated as a white solid.

α!_(D) ²⁵ +179.1° (c 0.92, chloroform).

¹ H NMR (300 MHz, CDCl₃) δ 7.91 (m, 3H), 7.61 (t, 1H), 7.50-7.31 (m,5H), 6.65 (s, 1H), 6.55 (d, 1H), 5.11 (q, 1H), 4.58 (m, 2H), 3.72 (s,3H), 3.50 (d, 1H), 3.26 (dd, 1H), 2.99 (dd, 1H), 1.51 (d, 3H), 1.05 (s,9H).

As the more polar fraction, 270 mg of the methyl ester of (R)-O-(-)-trans-7-chloro-5-(naphthalen-1-yl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!lacticacid was isolated as a white solid.

α!_(D) ²⁵ -132.1° (c 1.2, chloroform).

¹ H NMR (300 MHz, CDCl₃) δ 7.91 (d, 2H), 7.86 (d, 1H), 7.63-7.32 (m,6H), (s, 1H), 6.55 (d, 1H), 5.15 (q, 1H), 4.60 (m, 2H), 3.74 (s, 3H),3.48 (d, 1H), 3.15 (dd, 1H), 3.02 (dd, 1H), 1.47 (d, 3H), 1.05 (s, 9H).

EXAMPLE 18(-)-Trans-7-chloro-5-(naphthalen-1-yl-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid

Potassium carbonate (137 mg, 994 μmol) and water (0.5 mL) were added toa solution of the methyl esterof (-)-(R)-O-trans-7-chloro-5-(naphthalen-1-yl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!lacticacid (268 mg, 497 μmol) in methanol (5 mL). The resulting mixture washeated at 60° C. for 14 hours and concentrated under reduced pressure.The resulting residue was taken up in water, acidified with an aqueoussolution of 2N hydrochloric acid and extracted with ethyl acetate. Thecombined organics were dried over anhydrous sodium sulfate, filtered,concentrated under reduced pressure, and purified by flash columnchromatography (5% methanol/methylene chloride) to yield 208 mg (93%) ofa white solid.

α!_(D) ²⁵ -159.9° (c 1.0, chloroform).

EXAMPLE 19(+)-Trans-7-chloro-5-(naphthalen-1-yl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid

The title compound was prepared according to a procedure analogous tothat of Example 18.

89% yield.

α!_(D) ²⁵ +185.5° (c 1.1, chloroform).

EXAMPLE 20Trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepin-3-aceticacid EXAMPLE 20A(5-Chloro-2-neopentylamino)phenyl-(1-naphthyl)methylthiocilycolic acid

A mixture of 6.0 g (17 mmol)(5-chloro-2-neopentylamino)phenyl-(1-naphthyl)methanol, 6 mL (86 mmol)mercaptoacetic acid and 50 mL 6N aqueous hydrochloric acid was heated at100° C. for 5 hours under nitrogen. The reaction was cooled to roomtemperature, diluted with 200 mL water and stirred at room temperaturefor several hours. The mixture was then filtered, the solid was washedrepeatedly with water and air-dried to yield 7.26 g (quantitative yield)of the desired product as a tan colored solid.

¹ H NMR (CDCl₃) δ 0.9 (s, 9H); 2.86 (s, 2H); 3.24 (s, 2H); 6.46 (s, 1H);7.0 (d, 1H); 7.1 (c, 2H); 7.42 (c, 4H); 7.78 (c, 4H).

EXAMPLE 20B7-Chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepine

To a solution of 7.26 ((17 mmol)(5-chloro-2-neopentylamino)phenyl-(1-naphthyl)methylthioglycolic acid in800 mL dichloromethane was added 14.4 g (33.9 mmol)1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonateand the reaction mixture was stirred at room temperature under nitrogenovernight. TLC analysis indicated that the reaction had not gone tocompletion so another 3.6 g (8.5 mmol) of the carbodiimide was added andthe reaction mixture stirred at room temperature overnight.

The reaction mixture was then concentrated in vacuo and the residue waspartitioned between 200 mL ethyl acetate and 100 mL water. The ethylacetate layer was washed sequentially with 2×100 mL water and 100 mLbrine, dried over anhydrous sodium sulfate, filtered and concentrated invacuo. The residue (7.8 g) was chromatographed on 700 g silica gel ,eluting with 85:15 hexane/ethyl acetate to yield 4.84 g (69.5% yield) ofthe desired product.

¹ H NMR (CDCl₃) δ 1.11 (s, 9H); 3.08 (d, 1H); 3.34 (2d, 2H); 4.51 (d,1H); 6.60 (s, 1H); 6.78 (d, 1H); 7.28 (c, 2H); 7.4 (t, 1H); 7.5 (t, 1H);7.61 (t, 1H); 7.93 (t, 3H); 8.02 (d, 1H).

EXAMPLE 20C t-Butyl ester oftrans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepin-3-aceticacid

A solution of lithium diisopropylamide in cyclohexane 11.8 mL (17.7mmol) of a 1.5M solution! was added slowly to a stirred solution of 4.84g (11.8 mmol)7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5,-tetrahydro-4,1-benzothiazepinein 225 mL anhydrous tetrahydrofuran cooled to -70° C. under nitrogen.The solution was stirred at -70° C. for 45 min, then 2.1 mL (13.0 mmol)t-butyl bromoacetate was slowly added and the resulting solution wasallowed to warm to room temperature overnight. The reaction mixture wastreated with 300 mL saturated aqueous ammonium chloride solution and 100mL ethyl acetate and the organic phase separated. The aqueous phase wasextracted with 3×200 mL ethyl acetate and the combined organic extractswere washed sequentially with 300 mL water and 230 mL brine, dried overanhydrous sodium sulfate, filtered and concentrated in vacuo. Theresidue (6.0 g) was chromatographed on 500 g silica gel, eluting with9:1 hexane/ethyl acetate to yield 5.6 g (91% yield) of the titlecompound as a 5:2 mixture of cis and trans isomers.

A solution of 3.03 g (21.9 mmol) potassium carbonate in 60 mL water wasadded to a solution of 5.6 g (10.7 mmol) of the mixture of cis and transisomers of the title compound dissolved in 225 mL methanol and theresulting solution was heated at 60° C. for 90 minutes The reactionmixture was cooled to room temperature, then concentrated in vacuo.Water (100 ml) was added to the residue and the aqueous mixture wasextracted with 3×100 mL ethyl acetate. The combined ethyl acetatesolutions were washed sequentially with 100 mL water and 100 mL brine,dried over anhydrous sodium sulfate, filtered and concentrated in vacuo.The residue (5.15 g) was chromatographed on 500 g silica gel, elutingwith 9:1 hexane/ethyl acetate to yield 4.54 g (81 % yield) of the titlecompound as a white solid.

¹ H NMR (CDCl₃) δ 1.11 (s, 9H); 1.43 (s, 9H); 2.41 (q, 1H); 3.08 (q,1H); 3.41 (d, 1H); 3.8 (q, 1H); 4.49 (d, 1H); 6.62 (s, 1H); 6.79 (d,1H); 7.3-7.64 (c, 5H); 7.92 (d, 1H); 8.0 (d, 1H).

EXAMPLE 20C17-Chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepin-3-aceticacid (mixture of diastereomers)

A stirred mixture of 50.0 g (141 mmol) of(5-chloro-2-neopentylamino-phenyl)-naphthalen-1-yl-methanol, 27.58 g(184 mmol, 1.3 equivalents) of mercaptosuccinic acid, and 340 mL ofpropionic acid was heated to 130° C. with a nitrogen purge. After 48hours, the reaction mixture was cooled to room temperature giving aprecipitate, treated with 200 mL of water, cooled to -5° C. withstirring, and filtered giving 60.83 g (92% yield) of the title compoundas an off white solid.

The ¹ H NMR (CDCl₃) indicates three compounds in a 2:2:1 ratio,characteristic sets of peaks: 6.64 (s), 3.81 (dd), 1.11 (s); 6.73 (s),4.16 (dd), 1.13 (s); 5.69 (s), 3.59 (dd), 0.63 (s).

EXAMPLE 20DTrans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepin-3-aceticacid

Trifluoroacetic acid (38 ml) was added slowly at room temperature to astirred solution of 4.5 g of the t-butyl ester oftrans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepin-3-aceticacid in 38 mL dichloromethane. The resulting solution was stirred atroom temperature for 3 hours, then concentrated in vacuo. The residuewas triturated with diethyl ether and the solid was filtered to yield2.11 g of the title compound as a white solid. The filtrate wasconcentrated in vacuo and residue was triturated with diethyl ether andfiltered to yield a further 1.05 g of the title compound (86% totalyield).

¹ H NMR (CDCl₃) δ 1.12 (s, 9H); 2.62 (q, 1H); 3.19 (q, 1H); 3.43 (d,1H); 3.83 (q, 1H); 4.48 (d, 1H); 6.64 (s, 1H); 6.8 (d, 1H); 7.3-7.64 (c,5H); 7.94 (d, 3H); 8.0 (d, 1H).

EXAMPLE 20D1Trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepin-3-aceticacid

A solution of 30.0 g (64.1 mmol) of7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydrom4,1-benzothiazepin-3-aceticacid (mixture of diastereomers) in 120 mL of dry tetrahydrofuran wastreated with 22.0 mL of 25% sodium methoxide solution in methanol (96mmol, 1.5 equivalents). The reaction mixture was warmed to 40° C. for 6hours, cooled to room temperature, treated with 144 mL of 1Nhydrochloric acid followed by 350 mL of water, stirred overnight at roomtemperature, and filtered giving 29.10 g (97% yield) of the titlecompound as a pale peach-colored granular solid. 1 H NMR identical tothat of Example 20D.

EXAMPLE 21 Methyl ester of (-)-(S)-O-trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepin-3-acetyl!lacticacid and methyl ester of (+)-(S)-O-trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetahydro-4,1-benzothiazerin-3-acetyl!lacticacid

To a solution of 1.5 g (3.2 mmol)trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepin-3-aceticacid and 0.61 mL (6.4 mmol) (S)-methyl lactate in 30 mL dichloromethanecooled to 0° C. under nitrogen was added 1.1 g1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (5.8 mmol)and 45 mg 4-dimethylaminopyridine. The reaction mixture was stirred atroom temperature for 3.5 hours, then diluted with 80 mL dichloromethane.The resulting solution was washed sequentially with 70 mL 1N aqueoushydrochloric acid, 70 mL saturated aqueous sodium bicarbonate solutionand 70 mL brine, dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo. Flash chromatography of the residue (1.63 g) on600 g silica gel, eluting with 3:1 hexane/ethyl acetate, yielded 716 mgof the less polar diastereomer, 72 mg of the more polar diastereomer and739 mg of a mixture of the two diastereomers (86% total yield).

EXAMPLE 21A Methyl ester of (-)-(S)-O-trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepin-3-acetyl!lacticacid (less polar diastereomer)

¹ H NMR (CDCl₃) δ 1.10 (s, 9H); 1.49 (d, 3H); 2.60 (q, 1H); 3.25 (q,1H); 3.40 (d, 1H); 3.72 (s, 3); 3.87 (q, 1H); 4.47 (d, 1H); 5.08 (q,1H); 6.64 (s, 1H); 6.79 (d, 1H); 7.28 (m, 1H); 7.35-7.45 (m 3H); 7.50(t, 1H); 7.61 (t, 1H); 7.93 (d, 2H); 7.99 (t, 1H).

α!_(D) ²⁰ -261° (methanol)

EXAMPLE 21B Methyl ester of (+)-(S)-O-trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepin-3-acetyl!lacticacid (more polar diastereomer)

¹ H NMR (CDCl₃) δ 1.11 (s, 9H); 1.47 (d, 3H); 2.59 (q, 1H); 3.27 (q,1H); 3.41 (d, 1H); 3.75 (s, 3H); 3.87 (q, 1H); 4.48 (d, 1H); 5.10 (q,1H); 6.65 (s, 1H); 6.79 (d, 1H); 7.26-7.45 (m, 4H); 7.50 (t, 1H); 7.60(t, 1H); 7.92 (d, 2H); 7.99 (t, 1H).

α!_(D) ²⁰ +202° (methanol)

EXAMPLE 21C Methyl ester of (-)-(S)-O-trans-7-trifluoromethyl-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5tetrahydro-4,1-benzoxazepin-3-acetyl!lacticacid

A procedure similar to that described in Example 21 was used.

Less polar (-)-diastereomer

29% yield.

¹ H NMR (250 MHz, CDCl₃) δ 1.05 (s, 9H); 1.5 (d, 3H); 2.98 (q, 1H); 3.26(q, 1H); 3.57 (d, 1H); 3.71 (s, 3H); 4.54 (q, 1H); 4.59 (d, 1H); 5.09(q, 1H); 6.67 (s, 1H); 6.82 (s, 1H); 7.73 (t, 1H); 7.44 (2d, 2H); 7.62(m, 3H); 7.91 (t, 3H).

More polar (+)-diastereomer

23% yield.

¹ H NMR (250 MHz, CDCl₃) δ 1.04 (s, 9H): 1.45 (d, 3H); 2.99 (q, 1H);3.14 (q, 1H); 3.57 (d, 1H); 3.72 (s, 3H); 4.55 (t, 1H); 4.6 (d, 1H);5.11 (q, 1H); 6.68 (s, 1H); 6.82 (s, 1H); 7.3 ((t, 1H); 7.46 (m, 2H);7.6 (m, 3H); 7.84 (d, 1H); 7.92 (d, 2H).

EXAMPLE 22(-)-Trans-7-chloro-5-(1-naphthyl)-1-neopentyi-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepin-3-aceticacid

A solution of 269 mg(1.95 mmol) potassium carbonate in 8 mL water wasadded to a solution of 360 mg (0.65 mmol) methyl ester of (-)-(S)-O-trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepin-3-acetyl!lacticacid (less polar diastereomer) in 25 mL methanol. The resulting solutionwas heated at 60° C. for 2 hours, cooled to room temperature and thenconcentrated in vacuo. Water (10 ml) was added to the residue, theresulting solution was acidified with 1N aqueous hydrochloric acid andextracted with 3×30 mL ethyl acetate. The combined ethyl acetateextracts were washed with 70 mL brine, dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo to yield 290 mg (95% yield)of the title compound as a white solid.

¹ H NMR (CDCl₃) δ 1.12 (s, 9H); 2.57 (q, 1H); 3.18 (q, 1H); 3.42 (d,1H); 3.82 (q, 1H); 4.50 (d, 1H); 6.64 (s, 1H); 6.80 (d, 1H); 7.26-7.45(m, 3H); 7.51 (t, 1H); 7.61 (t, 1H); 7.93 (d, 3H); 7.99 (t, 1H).

α!_(D) ²⁰ -288° (methanol)

EXAMPLE 22A (R)-α-Methylbenzylammonium salt of(-)-trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepin-3-aceticacid

A mixture of 10.0 g (21.4 mmol) oftrans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepin-3-aceticacid, 224 mL of 95% ethanol, and 2.8 mL (21 mmol) of(R)-(+)-α-methylbenzylamine was heated to reflux and cooled with seedingof the title compound. The resulting slurry was stirred overnight atroom temperature. The solids were isolated and dissolved in 60 mL of 95%ethanol at reflux, stirred at reflux temperature for 5 minutes, andslowly cooled to room temperature with stirring overnight. Filtration ofthe white solid and vacuum drying yielded 3.98 g (29% yield) of thetitle compound as an ethanol solvate with a diastereomeric purity 99.8%according to chiral chromatography.

α!_(D) -217.3° (c 1.0, CHCl₃).

¹ H NMR (CDCl₃) δ 8.03-7.90 (m, 4H), 7.61-7.23 (m, 10H), 6.79 (d, 1H),6.62 (s, 1H), 5.00 (br s, 4H), 4.40 (d, 1H), 4.22 (q, 1H), 3.78 (dd,1H), 3.73 (q, 2H), 2.90 (dd, 1H), 2.32 (dd, 1H), 1.53 (d, 3H), 1.25 (t,3H), 1.08 (s, 9H).

EXAMPLE 22B(-)-Trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepin-3-aceticacid

The (R)-α-methylbenzylammonium salt of(-)-trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepin-3-aceticacid, ethanol solvate, 3.50 g (5.51 mmol), was treated with 35 mL ofethyl acetate and 17 mL of 1N hydrochloric acid with stirring at roomtemperature giving two homogeneous phases. The phases were separated,the aqueous phase was extracted with ethyl acetate (2×15 mL), and thecombined organic phases were concentrated under vacuum giving 2.48 g(96% yield) of the title compound as a white solid.

¹ H NMR identical to that of Example 22.

EXAMPLE 22C(-)-Trans-7-trifluoromethyl-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-aceticacid

A procedure similar to that described in Example 22 was used using theless polar (-)-diastereomer of Example 21C. 60% yield.

¹ H NMR (250 MHz, CDCl₃) identical to that of Example 54D.

α!_(D) ²⁰ -151° (c 1.0,methanol).

EXAMPLE 23(+)-Trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepin-3-aceticacid

Using a procedure analogous to that described in Example 22 but startingwith the methyl ester of (S)-O-(+)-trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepin-3-acetyl!lacticacid (more polar diastereomer), the title compound was obtained as awhite solid in quantitative yield.

¹ H NMR (CDCl₃) δ 1.12 (s, 9H); 2.57 (q, 1H); 3.19 (q, 1H); 3.42 (d,lh); 3.82 (q, 1H); 4.50 (d, 1H); 6.64 (s, 1H); 6.80 (d, 1H); 7.26-7.46(c, 3H); 7.51 (t, 1H); 7.61 (t, 1H); 7.93 (d, 3H); 7.99 (t, 1H).

α!_(D) ²⁰ +264° (methanol)

The title compounds of Examples 23A through 23C were prepared by aprocedure analogous to that described in Example 20A-20C.

EXAMPLE 23A t-Butyl ester oftrans-7-methyl-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzothiazepine-3-aceticacid

95% yield.

MS (PCl): 505 (M+2H⁺).

¹ H NMR (250 MHz, CDCl₃) δ 8.00 (m, 2H), 7.90 (m, 2H), 7.61-7.28 (m,4H), 7.10 (dd, 1H), 6.64 (s, 1H), 6.59 (d, 1H), 4.47 (d, 1H), 3.80 (dd,1H), 3.44 (d, 1H), 3.07 (dd, 1H), 2.39 (dd, 1H), 2.09 (s, 3H), 1.42 (s,9H), 1.10 (s, 9H).

EXAMPLE 23B t-Butyl ester oftrans-7-methoxy-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzothiazepine-3-aceticacid

82% yield.

MS (PCl): 521 (M+2H⁺).

¹ H NMR (300 MHz, CDCl₃) δ 8.00 (m, 2H), 7.88 (dd, 2H), 7.59-7.32 (m,4H), 6.82 (dd, 1H), 6.63 (s, 1H), 6.34 (d, 1H), 4.46 (d, 1H), 3.84 (dd,1H), 3.54 (s, 3H), 3.40 (d, 1H), 3.07 (dd, 1H), 2.39 (dd, 1H), 1.42 (s,9H), 1.11 (s, 9H).

EXAMPLE 23C t-Butyl ester oftrans-7-chloro-5-(4-methoxyrarphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzothiazepine-3-aceticacid

34% yield.

MS (PCl): 555 (M+2H⁺).

¹ H NMR (250 MHz, CDCl₃) δ 8.35 (d, ₁ H), 7.88 (m, 2H), 7.51-7.25 (m,4H), 6.91 (d, 1-H), 6.82 (d, 1H), 6.53 (s,1H), 4.48 (d, 1H), 4.07 (s,3H), 3.76 (dd,1H), 3.39(d, 1H), 3.07 (dd, 1H), 2.39 (dd, 1H), 1.42 (s,9H), 1.10 (s, 9H).

EXAMPLE 23D Ethyl ester oftrans-7-acetyl-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzothiazepine-3-aceticacid

Trans-7-bromo-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzothiazepine-3-aceticacid (Example 23I; 3.19 g, 6.23 mmol), concentrated sulfuric acid (10drops) and ethanol (53 mL) were heated at reflux for 18 h, cooled toambient temperature and concentrated under reduced pressure. Theresulting oil was diluted with ethyl acetate, washed with saturatedaqueous sodium bicarbonate and saturated aqueous sodium chloride, driedover anhydrous sodium sulfate and concentrated under reduced pressure toprovide the ethyl ester oftrans-7-bromo-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzothiazepine-3-aceticacid as a white foam in quantitative yield. The ethyl ester oftrans-7-bromo-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzothiazepine-3-aceticacid (1.00 g) was converted to the title compound in a manner similar tothat described in Example 6F to provide 406 mg (44%) of the titlecompound as a white powder.

MS (PCl): 504 (M+H⁺).

EXAMPLE 23D1 Ethyl ester oftrans-7-(thiazol-2-yl)-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzothiazepine-3-aceticacid

A mixture of the ethyl ester oftrans-7-bromo-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzothiazepine-3-aceticacid (200 mg, 370 μmol), 2-tributylstannylthiazole (253 mg, 407 μmol;60% pure), bis(triphenylphosphine)palladium (II) chloride (2.6 mg,3.7μmol) and toluene (450 μL) was heated at 100° C. for 20 hours.Rection mixture cooled to ambient temperature, absorbed onto silica geland purified by flash column chromatography (4:1 hexanes/ethyl acetate)to provide 97 mg (48%) the title compound as a white foam that wastriturated with hexanes.

MS (PCl): 545 (M+H⁺).

¹ H NMR (300 MHz, CDCl₃) δ 8.10-7.89 (m, 5H), 7.72 (d, 1H), 7.64 (t,1H), 7.52-7.37 (m, 4H), 7.19 (d, 1H), 6.72 (s, 1H), 4.52 (d, 1H), 4.12(qd, 2H), 3.92 (dd, 1H), 3.49 (d, 1H), 3.18 (dd, 1H), 2.48 (dd, 1H),1.24 (t, 3H), 1.12 (s, 9H).

The title compounds of Examples 23E through 23H1 were prepared by aprocedure analogous to that described in Example 20D.

EXAMPLE 23ETrans-7-methyl-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzothiazepine-3-aceticacid

81% yield.

MS (PCl): 448 (M+H⁺).

¹ H NMR (250 MHz, CDCl₃) δ 11.90 (br s, 1H), 7.96 (m, 4H), 7.63-7.26 (m,4H), 7.15 (dd,1H), 6.64 (d, 2H), 4.47 (d,1H), 3.86 (dd,1H), 3.48 (d,1H),3.20 (dd,1H), 2.64 (dd, 1H), 2.12 (s, 3H), 1.12 (s, 9H).

EXAMPLE 23FTrans-7-methoxy-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzothiazepine-3-aceticacid

88% yield.

MS (PCl): 464 (M+H⁺).

¹ H NMR (300 MHz, CDCl₃) δ 8.00 (d, 2H), 7.89 (d, 2H), 7.60-7.30 (m,4H), 6.84 (dd, 1H), 6.64 (s, 1H), 6.35 (d, 1H), 4.47 (d, 1H), 3.85 (dd,1H), 3.55 (s, 3H), 3.40 (d, 1H), 3.13 (dd, 1H), 2.59 (dd, 1H), 1.11 (s,9H).

EXAMPLE 23GTrans-7-chloro-5-(4-methoxynaphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzothiazepine-3-aceticacid

92% yield.

MS (PCl): 498 (M+H⁺).

¹ H NMR (250 MHz, CD₃ OD) δ 12.44 (br s, 1H), 8.28 (d, 1H), 7.79 (m,3H), 7.51 (m, 3H), 7.15 (d, 1H), 6.64 (d, 1H), 6.39 (s, 1H), 4.26 (d,1H), 4.04 (s, 3H), 3.62 (m, 2H), 2.83 (dd, 1H), 2.50 (m, 1H), 1.01 (s,9H).

EXAMPLE 23HTrans-7-acetyl-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzothiazepine-3-aceticacid

77% yield.

MS (PCl): 476 (M+H⁺).

¹ H NMR (300 MHz, CDCl₃) δ 8.04 (d, 1H). 7.94 (m, 4H), 7.65-7.39 (m,5H), 6.70 (s, 1H), 4.53 (d, 1H), 3.79 (dd, 1H), 3.49 (d, 1H), 3.19 (dd,1H), 2.57 (dd, 1H), 2.28 (s, 3H), 1.11 (s, 9H).

EXAMPLE 23H1Trans-7-(thiazol-2-yl)-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzothiazepine-3-aceticacid

47% yield.

MS (PCl): 517 (M+H⁺).

¹ H NMR (300 MHz, CD₃ OD) δ 8.08 (d, 1H), 7.96 (m, 3H), 7.88 (s, 3H),7.66 (m, 2H), 7.44 (m, 3H), 6.67 (s, 1H), 4.43 (d, 1H), 3.87 (dd,1H),.3.63 (d, 1H), 3.00 (dd, 1H), 2.51 (dd, 1H), 1.11 (s, 9H).

EXAMPLE 23ITrans-7-bromo-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzothiazepine-3-aceticacid

Prepared in a manner similar to that described in Example 20C1, with theaddition of the mercaptosuccinic acid taking place in glacial aceticacid followed by concomitant cyclization and epimerization inchlorobenzene in the presence of catalytic p-toluenesulfonic acid and 3Å seives.

20% yield.

MS (PCl): 514 (M+H⁺).

¹ H NMR (250 MHz, CDCl₃) δ 7.96 (m, 4H), 7.63-7.28 (m, 5H), 6.95 (d,1H), 6.63 (s, 1H), 4.48 (d, 1H), 3.81 (dd, 1H), 3.41 (d, 1H), 3.15 (dd,1H), 2.59 (dd, 1H), 1.11 (s, 9H).

EXAMPLE 24 Methyl ester of N-trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl!-L-proline

To a solution of 208 mg (0.46 mmol)trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-aceticacid and 80 mg (0.48 mmol) L-proline methyl ester hydrochloride in 5 mLdimethylformamide cooled to 0° C. was added 0.08 mL (0.52 mmol) diethylcyanophosphonate followed by 0.13 mL (0.92 mmol) triethylamine. Thereaction mixture was stirred at room temperature for 2 hours, thenpoured into 50 mL ice water. The resulting mixture was extracted with3×40 mL ethyl acetate and the combined ethyl acetate extracts werewashed sequentially with 50 mL 1N aqueous hydrochloric acid, 50 mLsaturated sodium bicarbonate, 3×50 mL water and 50 mL brine. The ethylacetate solution was dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo. The resulting oil was chromatographed- on 200 gsilica gel, eluting with 1:1 hexane/ethyl acetate to yield 220 mg (85%yield) of the title compound as a white amorphous solid.

¹ H NMR (CDCl₃): δ 1.03, 1.04 (2s, 9H); 1.8-2.34 (c, 3H); 2.75-3.3 (c,3H); 3.42-3.78 c, d at 3.47(1H) and 2s at 3.7, 3.73 (3H), total 6H!;4.43-4.61 (c, 2H); 4.73 (c, 1H); 6.51 (2d, 1H); 6.6, 6.62 (2s, 1H);7.28-7.64 (c, 6H); 7.7-7.96 (c and d at 9.91, total 3H).

The title compounds of Examples 24A through 31N were prepared by aprocedure analogous to that described in Example 24.

EXAMPLE 24A Methyl ester of (-)-N-trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl!-L-proline

Using the procedure of Example 24 but starting with(-)-trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-aceticacid (Example 18), the title compound was obtained as a white solid in59% yield.

¹ H NMR (CDCl₃): 6 1.03 (s, 9H); 1.93-2.26 (c, 3H); 2.82 (q, 1H); 3.23(q, 1H); 3.47 (d, 1H); 3.7 (c and s, 5H); 4.47 (m, 2H); 4.54 (d, 1H);4.72 (m, 1H); 6.52 (d, 1H); 6.61 (s, 1H); 7.3-7.56 (c, 5H); 7.61 (t,1H); 7.92 (d, 3H).

α!_(D) ²⁰ -199° (methanol)

EXAMPLE 25 Ethyl ester of N-trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl!isonipecoticacid

77% yield

¹ H NMR (CDCl₃): δ 1.04 (s, 9H); 1.26 (c, 3H); 1.55-2.0 (c, 3H); 2.5 (c,1H); 2.83 (c, 2H); 3.15 (c, 2H); 3.49 (d, 1H); 3.92 (c, 1H); 4.13 (c,2H); 4.35 (c, 1H); 4.58 (2d, 1H); 4.7 (c, 1H); 6.52 (s, 1H); 6.61 (s,1H); 7.3-7.62 (c, 6H); 7.84 (m, 1H); 7.91 (d, 2H).

EXAMPLE 25A Ethyl ester of (-)-N-trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl!isonipecoticacid

Using a procedure analogous to that of Example 24A, the title compoundwas obtained as a white solid in 73% yield.

¹ H NMR identical to that of Example 25.

EXAMPLE 26 Ethyl ester of N-trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl!nipecoticacid

77% yield

¹ H NMR (CDCl₃); δ 1.04 (s, 9H); 1.25 (c, 3H); 1.55-1.85 (c, 3H); 2.06(c, 1H); 2.3-3.45 (c, 6H); 3.5 (d, 1H); 3.95 (c, 1H); 4.13 (q, 2H), 4.57(d, 1H); 4.7 (c, 1H); 6.52 (s, 1H), 6.62 (s, 1H); 7.3-7.62 (c, 6H); 7.84(b, 1H); 7.92 (d, 2H).

EXAMPLE 27 Methyl ester of N-trans-7-chloro-5-(1-naphthyl)-1-neoentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl!-L-S-methylcysteine

58% yield

Flash chromatography of 223 mg of the crude product on 50 g silica gel,eluting with 6:4 hexane/ethyl acetate, yielded 67.2 mg of the less polardiastereomer, 46.2 mg of the more polar diastereomer and 33.3 mg of amixture of the two diastereomers.

Less polar diastereomer

¹ H NMR (CDCl₃): δ 1.04 (s, 9H); 2.06 (d, 3H), 2.77-3.07 (m, 4H); 3.47(d, 1H); 3.72 (s, 3H); 4.51, 4.53, 4.55, 4.58 (2d, 2H); 4.8 (c, 1H);6.53 (d, 1H); 6.64 (s, 1H); 6.73 (d, 1H); 7.33 (c, 3H); 7.47 (c, 2H);7.6 (t, 1H); 7.9 (t, 3H).

More polar diastereomer

¹ H NMR (CDCl₃): δ 1.04 (s, 9H); 1.97 (s, 3H); 2.77-3.04 (c and d at2.9, total 4H); 3.48 (d, 1H); 3.76 (s, 3H); 4.58 (c, 2H); 4.81 (c, 1H);6.53 (d, 1H); 6.63 (s, 1H); 6.77 (d, 1H); 7.36 (c, 3H); 7.42-7.62 (m,3H); 7.86 (d, 1H); 7.91 (d, 2H).

EXAMPLE 27A Methyl ester of (-)-N-trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl!-L-S-methylcysteine

Using a procedure analogous to Example 24A the title compound wasobtained as a white solid in 68% yield.

¹ H NMR identical to that of less polar diastereomer in Example 27.

α!_(D) ²⁰ -190° (methanol).

EXAMPLE 28 α,β-Dimethyl ester of N-trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5etrahydro-4,1-benzoxazepin-3-acetyl!-L-asparticacid

59% yield

¹ H NMR (CDCO₃) δ 1.03, 1.04 (2s, 9H); 2.8 (c, 2H); 2.89-3.08 (c, 2H);3.47 (d, 1H); 3.58, 3.67, 3.69, 3.75 (4s, 6H); 4.56 (c, 2H); 4.86 (c,1H); 6.52 (s, 1H); 6.62 (s, 1H); 6.83 (m, 1H); 7.35 (c, 3H); 7.47 (m,2H); 7.6 (c, 1H); 7.85 (m, 1H); 7.91 (d, 2H).

EXAMPLE 29 α,γ-Dimethyl ester of N-trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl!-L-glutamicacid

52% yield

¹ H NMR (CDCl₃) δ 1.03 (s, 9H); 1.99 (m, 1H); 2.1-2.45 (c, 3H); 2.77(q,1H); 2.94 (q, 1H); 3.47 (d, 1H); 3.57, 3.66, 3.69, 3.73 (4s, 6H);4.58 (c, 3H); 6.51 (d, 1H); 6.52, 6.62 (2d, total 1H); 6.61 (s, 1H);7.35 (c, 3H); 7.47 (m, 2H); 7.58 (t, 1H); 7.84 (t, 1H); 7.91 (d, 2H).

EXAMPLE 30 β-t-Butyl ester-α-methyl ester of N-trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl!-L-asparticacid

71% yield

Column chromatography of 210 mg of crude product on 200 g silica gel,eluting with 7:3 hexane/ethyl acetate, yielded 41 mg of the less polardiastereomer, 33 mg of the more polar diastereomer and 69 mg of amixture of the two diastereomers.

EXAMPLE 30A

Less polar diastereomer

¹ H NMR (CDCl₃): δ 1.03 (s, 9H); 1.42 (s, 9H); 2.66-3.0 (c, 4H); 3.47(d, 1H); 3.69 (s, 3H); 4.55 (c, 2H); 4.85 (c, 1H); 6.51 (d, 1H); 6.62(s, 1H), 6.78 (d, 1H); 7.25-7.5 (c, 6H); 7.59 (t, 1H); 7.9 (c, 3H).

EXAMPLE 30B

More polar diastereomer

¹ H NMR (CDCl₃): δ 1.04 (s, 9H); 1.36 (s, 9H); 2.62-3.0 (m, 4H); 3.47(d, 1H); 3.74 (s, 3H); 4.58 (c, 2H); 4.82 (c, 1H); 6.51 (d, 1H); 6.62(s, 1H); 6.80 (d, 1H); 7.35 (m, 4H); 7.48 (q, 1H); 7.59 (t, 1H); 7.83(d, 1H); 7.91 (d, 2H).

EXAMPLE 31 γ-t-Butyl ester-α-methyl ester of N-trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl!-L-glutamicacid

80% yield

Column chromatography of 220 mg of crude product on 200 g silica gel,eluting with 7:3 hexane/ethyl acetate, yielded 97 mg of the less polardiastereomer, 70 mg of the more polar diastereomer and 12 mg of amixture of the two diastereomers.

EXAMPLE 31A

Less polar diastereomer

¹ H NMR (CDCl₃): δ 1.04 (s, 9H); 1.44 (s, 9H); 1.95 (m, 1H); 2.18 (m,1H); 2.3 (m, 2H); 2.77 (q, 1H); 2.94 (q, 1H); 3.47 (d, 1H); 3.69 (s,3H); 4.57 (c, 3H); 6.51 (s, 1H); 6.54 (d, 1H); 6.61 (s, 1H); 7.29-7.51(c, 5H); 7.59 (t, 1H); 7.86 (d, 1H); 7.91 (d, 2H).

EXAMPLE 31B

More polar diastereomer:

¹ H NMR (CDCl₃): δ 1.04 (s, 9H); 1.39 (s, 9H); 1.94 (m, 1H); 2.11 (m,1H); 2.27 (m, 2H); 2.76 (q, 1H); 2.95 (q, 1H); 3.47 (d, 1H); 3.73 (s,3H); 4.56 (c, 3H); 6.52 (s, 1H); 6.58 (d, 1H); 6.62 (s, 1H); 7.35 (c,3H); 7.48 (q, 2H); 7.6 (t, 1H); 7.84 (d, 1H); 7.91 (d, 2H).

EXAMPLE 31C Methyl ester of N-trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl!-1-amino-1-cyclopentanecarboxylicacid

64% yield

¹ H NMR (250 MHz, CDCl₃) δ 1.04 (s, 9H); 1.77 (c, 4H); 1.94 (c, 2H);2.23 (c, 2H); 2.73 (q, 1H); 2.89 (q, 1H); 3.47 (d, 1H); 3.67 (s, 3H),4.55 (c, 2H); 6.32 (s, 1H); 6.52 (d, 1H); 6.63 (s, 1H); 7.35 (m, 3H);7.48 (q, 2H); 7.58 (t, 1H); 7.9 (t, 3H).

EXAMPLE 31D Methyl ester of N-trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl!-1-amino-1-cyclopropanecarboxylicacid

51% yield.

¹ H NMR (250 MHz, CDCl₃) δ 1.04 (s, 9H); 1.6 (c, 4H); 2.73 (q, 1H); 2.93(q, 1H); 3.48 (d, 1H); 3.66 (s, 3H); 4.56 (d) and 4.58 (m) (total 2H);6.4 (s, 1H); 6.53 (d, 1H); 6.62 (s, 1H); 7.35 (c, 3H); 7.5 (m, 2H); 7.6(t, 1H); 7.87 (d, 1H); 7.92 (d, 2H).

EXAMPLE 31E Ethyl ester of N-(-)-trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl!-L-methionine

Less polar diastereomer

32% yield.

¹ H NMR (250 MHz, CDCl₃) δ 1.04 (s, 9H); 1.27 (t, 3H); 1.98 (m, 1H); 2.1(s) and 2.17 (m) (total 4H); 2.5 (c, 2H); 2.8 (q, 1H); 2.96 (q, 1H);3.47 (d, 1H); 4.17 (q, 2H); 4.55 (c, 2H); 4.67 (m, 1H); 6.5 (d) and 6.52(d) (total 2H); 6.62 (s, 1H); 7.3-7.4 (c, 3H); 7.42-7.51 (c, 2H); 7.59(t, 1H); 7.86 (d, 1H); 7.91 (d, 2H).

EXAMPLE 31F Methyl ester of N-trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl!-cis-4-hydroxy-D-proline

58% yield.

¹ H NMR (250 MHz, CDCl₃) δ 1.03 (2s, 9H); 2.03-2.4 (c, 2H); 2.85 (q,1H); 3.17 (q, 1H); 3.46 (d, 1H); 3.65-3.88 (c and 2S at 3.78, 3.79,total 5H); 4.22 (c, 1H); 4.46-4.6 (c, 2H); 4.7 (c, 1H); 6.53 (d, 1H);6.61 (s, 1H); 7.3-7.65 (c, 6H); 7.74 (d) and 7.9 (c) (total 3H).

EXAMPLE 31G Methyl ester of N-trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl!trans4-hydroxy-L-proline

44% yield.

¹ H NMR (250 MHz, CDCl₃) δ 1.02, 1.03 (2s, 9H); 2.28(c, 2H); 2.54 (d,1H); 2.77, 2.83 (2q, 1H); 3.0, 3.2 (2q, 1H); 3.45, 3.46 (2d, 2H); 3.73(2s, 3H); 4.6 (c, 3H); 4.7 (c, 1H); 6.52 (s, 1H); 6.61 (s, 1H); 7.3-7.64(c, 6H); 7.8-7.95 (m, 3H).

EXAMPLE 31H Methyl ester of N-trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl!4-azetidinecarboxylicacid

25% yield.

¹ H NMR (250 MHz, CDCl₃) δ 1.03 (2s, 9H); 2.6 (q, 1H); 2.68 (d, 1H); 2.8(q, 1H); 3.47 (d, 1H); 3.71, 3.74 (2s, 3H); 4.17 (c, 2H); 4.35 (c, 2H);4.47-4.65 (m, 2H); 6.51 (t, 1H); 6.61 (s, 1H); 7.36 (c, 3H); 7.4-7.67(c, 3H); 7.81 (q; 1H); 7.92 (d, 2H);

EXAMPLE 31I Methyl ester of (-)-N-trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl!-D-proline

Using a procedure similar to that of Example 24A the title compound wasobtained as a white solid in 44% yield.

¹ H NMR (250 MHz, CDCl₃) δ 1.04 (s, 9H); 1.8-2.4 (C, 4H); 2.86-3.16 (cand q at 2.95, total 2H); 3.42-3.75 (c and s at 3.72, total 6H); 4.53(c) and 4.58 (d) (total 2H); 4.72 (c, 1H); 6.5 (d, 1H); 6.62 (s, 1H);7.28-7.64 (c, 6H); 7.77 (d, 1H); 7.91 (d, 2H).

α!_(D) ²⁰ -135° (c 1.0, CHCl₃).

EXAMPLE 31J Methyl ester of (-)-N-trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl!-L-pipecolinicacid

Using a procedure similar to that of Example 24A the title compound wasobtained as a white solid in 79% yield.

¹ H NMR (250 MHz, CDCl₃) δ 1.04 (s, 9H); 1.5-1.78 (C, 5H); 2.2 (c, 1H);2.83 (q, 1H); 3.22 (m, 1H); 3.36 (q, 1H); 3.5 (d, 1H); 3.7 (s, 3H); 3.87(c, 1H); 4.58 (d, 1H); 4.68 (q, 1H); 5.26 (c, 1H); 6.51 (d, 1H); 6.62(s, 1H); 7.3-7.64 (c, 6H); 7.92 (d, 3H).

EXAMPLE 31K Ethyl ester of (-)-N-trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl!-(-)-nipecoticacid

Using a procedure similar to that of Example 24A the title compound wasobtained as a white solid in 69% yield.

¹ H NMR (250 MHz, CDCl₃) identical to that of Example 26 except for theprotons at 1.256 which are a quartet.

α!_(D) ²⁰ -119.6° (c 0.7, MeOH).

EXAMPLE 31L Ethyl ester of N-trans-7-trifluoromethyl-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl!nipecoticacid

76% yield.

¹ H NMR (250 MHz, CDCl3) δ 1.04 (s, 9H); 1.25 (c, 3H); 1.5-1.85 (c, 3H);2.05 (c, 1H); 2.4-3.5 (c, 6H); 3.58 (d, 1H); 3.82-4.2 (c and q at 4.13,total 3H); 4.65 (d, 1H); 4.68 (c, 1H); 6.66 (s, 1H); 6.82 (d, 1H); 7.32(c, 1H); 7.46 (t, 2H); 7.6 (s and c, total 3H); 7.87 (t, 1H); 7.92 (d,2H).

EXAMPLE 31M Ethyl ester of N-trans-7-trifluoromethyl-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl!isonipecoticacid

67% yield.

¹ H NMR (250 MHz, CDCl₃) δ 1.04 (s, 9H); 1.25 (c, 3H); 1.52-1.98 (c,4H); 2.5 (c, 1H); 2.82 (c, 2H); 3.15 (c, 2H); 3.58 (d, 1H); 3.9 (c, 1H);4.1 (c, 2H); 4.34 (c, 1H); 4.6 (2d, 1H); 4.67 (c, 1H); 6.66 (s, 1H);6.82 (s, 1H); 7.32 (t, 1H); 7.48 (c, 2H); 7.6 (s and c, total 3H); 7.86(t, 1H); 7.92 (d, 2H);

EXAMPLE 31N Methyl ester of N-trans-7-trifluoromethyl-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl!-L-proline

76% yield.

¹ H NMR (250 MHz, CDCl₃ 6 1.03, 1.04 (2s, 9H); 1.8-2.36 (c, 3H);2.77-3.3 (c, 3H); 3.5-3.75 c,d (1H) at 3.55 and 2 s (3H)at 3.69 and 3.72(total 6H)!; 4.42-4.76 (c, 3H); 6.65 (s, 1H); 6.81 (d, 1H); 7.35 (m,1H); 7.46 (m, 2H); 7.6 (c, 3H); 7.78-7.95 (c and d at 7.92, total 3H);

EXAMPLE 32 Ethyl ester of N-trans-7-chloro-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!isonipecoticacid

4-Dimethylaminopyridine (2.3 mg, 19 μmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (72 mg, 374μmol) and ethyl isonipecotate (35 mg, 225 μmol, 35 μL) were addedsequentially to a solution oftrans-7-chloro-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-aceticacid (84 mg, 187 μmol) and methylene chloride (3 mL). After stirring 18hours at ambient temperature, the reaction mixture was diluted withethyl acetate, washed with water and saturated aqueous sodium chloride,dried over anhydrous magnesium sulfate, filtered, concentrated underreduced pressure, and purified by flash column chromatography (2:1hexanes/ethyl acetate) to produce 92 mg (84%) of the title compound as awhite solid.

MS (PCl): 577.

¹ H NMR (250 MHz, CD₃ OD) δ 8.31 (d, 1H), 7.87 (s, 1H), 7.83 (dd, 1H),7.57-7.25 (m, 4H), 6.97 (dd, 1H), 6.88 (d, 1H), 6.47 (s, 1H), 6.33 (d,1H), 4.33 (br t, 1H), 4.03 (m, 2H), 3.57 (m, 2H), 3.52 (d, 1H), 3.06 (m,1H), 2.89 (d, 1H), 2.52 (m, 2H), 2.26 (m, 2H), 1.99 (m, 1H), 1,83 (m,1H), 1.57 (m, 1H), 1.46-0.83 (m, 3H), 1.18 (q, 3H), 1.08 (s, 9H).

The title compounds of Examples 32A through 32N were prepared by aprocedure analogous to that described in Example 32.

EXAMPLE 32A Ethyl ester of N-trans-7-chloro-5-(4-methoxynaphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-acetyl!isonipecoticacid

93% yield.

MS (PCl): 621.

¹ H NMR (250 MHz, CDCl₃) δ 8.35 (d, ₁ H), 8.11 (t, ₁ H), 7.48-7.29 (m,5H), 6.90 (t, 1H), 6.57 (t, 1H), 6.52 (s, 1H), 4.66 (m, 1H), 4.56 (appd, 1H), 4.36 (brt, 1H), 4.13 (qd, 2H), 4.07 (s, 3H), 3.92 (m, 1H), 3.47(d, 1H), 3.14 (m, 2H), 2.81 (m, 2H), 2.49 (m, 1H), 1.76 (m, 4H), 1.24(m, 3H), 1.02 (s, 9H).

EXAMPLE 32B Ethyl ester of N-trans-7-chloro-5-(4-methoxynaphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-acetyl!nipecoticacid

95% yield.

MS (PCl): 621.

EXAMPLE 32C Ethyl ester of N-trans-7-chloro-5-(4-methoxynaphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzothiazepine-3-acetyl!isonipecoticacid

94% yield.

MS (PCl): 638 (M+2H⁺).

¹ H NMR (300 MHz, CDCl₃) δ 6.90 (dd, 1H), 6.80 (d, 1H), 6.54 (s, 1H),4.05 (s, 3H), 1.08 (s, 9H).

EXAMPLE 32D Ethyl ester of N-trans-7-methyl-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-acetyl!isonipecoticacid

92% yield.

MS (PCl): 572 (M+2H⁺).

¹ H NMR (300 MHz, CDCl₃) δ 6.62 (s, 1H), 6.30 (s, 1H), 3.49 (d, 1H),1.95 (s, 3H), 1.01 (s, 9H).

EXAMPLE 32E Ethyl ester of N-trans-7-methyl-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-acetyl!nipecoticacid

99% yield.

MS (PCl): 572 (M+2H⁺).

¹ H NMR (300 MHz, CDCl₃) δ 6.62 (s, 1H), 6.31 (s, 1H), 3.49 (d, 1H),₁1.96 (s, 3H), 1.01 (s, 9H).

EXAMPLE 32F Methyl ester of N-trans-7-methyl-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-acetyl!-L-proline

99% yield.

MS (PCl): 544 (M+2H⁺).

¹ H NMR (250 MHz, CDCl₃, diastereomeric mixture) δ 6.63 and 6.61 (2s,1H), 6.33 and 6.31 (2d, 1H), 2.01 and 1.99 (2s, 3H), 1.03 (s, 9H).

EXAMPLE 32G Ethyl ester of N-trans-7-methyl-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzothiazeine-3-acetyl!isonipecoticacid

89% yield.

MS (PCl): 587 (M+H⁺).

¹ H NMR (300 MHz, CDCl₃) δ 7.08 (d,1H), 6.65 (s,1H), 6.56 (s,1H), 2.06(s, 3H), 1.09 (s, 9H).

EXAMPLE 32H Ethyl ester of N-trans-7-methyl-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzothiazepine-3-acetyl!nipecoticacid

93% yield.

MS (PCl): 587 (M+H⁺).

¹ H NMR (300 MHz, CDCl₃) δ 7.08 (d, 1H), 6.65 (s, 1H), 6.56 (s, 1H),2.06 (s, 3H), 1.09 (s, 9H).

EXAMPLE 32I Methyl ester of N-trans-7-methyl-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzothiazepine-3-acetyl!-L-proline

98% yield.

MS (PCl): 560 (M+2H⁺).

¹ H NMR (250 MHz, CDCl₃, diastereomeric mixture) δ 6.65 (m, 1H), 6.57(d, 1H), 2.07 and 2.05 (2s, 3H), 1.10 and 1.09 (2s, 9H).

EXAMPLE 32J Ethyl ester of N-trans-7-methoxy-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-acetyl!isonipecoticacid

69% yield.

MS (PCl): 588 (M+2H⁺).

¹ H NMR (300 MHz, CDCl₃) δ 6.86 (dd, 1H), 6.63 (s, 1H), 6.06 (t, 1H),3.46 (s, 3H), 1.03 (s, 9H).

EXAMPLE 32K Ethyl ester of N-trans-7-methoxy-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-acetyl!nipecoticacid

97% yield.

MS (PCl): 588 (M+2H⁺).

¹ H NMR (300 MHz, CDCl₃) δ 6.86 (dd, 1H), 6.63 (s, 1H), 6.07 (m, 1H),3.46 (s, 3H), 1.03 (s, 9H).

EXAMPLE 32L Methyl ester of N-trans-7-methoxy-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-acetyl!-L-proline

90% yield.

MS (PCl): 560 (M+2H⁺).

¹ H NMR (300 MHz, CDCl₃) δ 6.84 (dd, 1H), 6.62.(s, 1H), 6.05 (dd, 1H),1.02 (s, 9H).

EXAMPLE 32M Ethyl ester of N-trans-7-methoxy-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzothiazepine-3-acetyl!isonipecoticacid

77% yield.

MS (PCl): 604 (M+2H⁺).

¹ H NMR (300 MHz, CDCl₃) δ 6.80 (dd, 1H), 6.64 (s, 1H), 6.32 (d, 1H),3.53 (s, 3H), 1.10 (s, 9H).

EXAMPLE 32N Ethyl ester of N-trans-7-acetyl-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzothiazepine-3-acetyl!isonipecoticacid

92% yield.

MS (PCl): 615 (M+H⁺).

¹ H NMR (300 MHz, CDCl3) δ 6.70 (s, 1H), 2.27 (s, 3H), 1.09 (s, 9H).

EXAMPLE 33 α,β-Dimethyl ester of N-trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepin-3-acetyl!-L-asparticacid

71 % yield

The procedure of Example 24 was followed with the exception thattrans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepin-3-aceticwas used in placeoftrans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-aceticacid.

¹ H NMR (CDCl₃) δ 1.09, 1.10 (2s, 9H); 2.43 (m, 1H); 2.76-2.9 (m, 1H);2.94-3.12 (m, 2H); 3.38 (d, 1H); 3.66, 3.72, 3.73, 3.77 (4s, 6H); 3.9(m, 1H); 4.48 (q, 1H); 4.8 (m, 1H); 6.62 (d, 1H); 6.77 (s, 1H); 7.27 (m,1H); 7.39 (m, 2H); 7.49 (t, 1H); 7.59 (t, 1H); 7.89-8.04 (c and d at7.92, total 4H).

The title compounds of Examples 34 through 37D were prepared by aprocedure analogous to that described in Example 33, with the exceptionof 35B.

EXAMPLE 34

α,γ-Dimethyl ester of N-trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazebin-3-acetyl!-L-glutamicacid

49% yield

¹ H NMR (CDCl₃) δ 1.09, 1.1 (2s, 9H); 1.99 (c, 1H); 2.2 (c, 1H); 2.39(c, 3H); 3.01 (m, 1H); 3.38 (m, 1H); 3.64, 3.71, 3,73, 3.75 (4s, 6H);3.9 (m, 1H); 4.48 (q, 1H); 4.57 (c, 1H); 6.42, 6.56 (2d, 1H); 6.62 (d,1H); 6.77 (d, 1H); 7.27 (m, 1H); 7.39 (m, 2H); 7.49 (t, 1H); 7.59 (t,1H); 7.92 (d, 3H); 7.98 (c, 1H).

EXAMPLE 35 Ethyl ester of (-)-N-trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepin-3-acetyl!isonipecoticacid

56% yield

¹ H NMR (CDCl₃) δ 1.10(s, 9H); 1.25 (c, 3H); 1.5-2.0 (c, 4H); 2.38 (d,H); 2.5 (c, 1H); 2.83 (c, 1H); 3.05-3.3 (c, 2H); 3.41 (d, 1H); 3.84 (c,1H); 3.97 (d, 1H); 4.15 (m, 2H); 4.3 (c, 1H); 4.5 (2d, 1H); 6.64 (s,1H); 6.77 (d, 1H); 7.29 (d, 1H); 7.41 (t, 2H); 7.5 (t, 1H); 7.6 (t, 1H);7.91, 7.93, 7.96, 8.0, 8.02 (m, 4H).

EXAMPLE 35A Ethyl ester of (-)-N-trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepin-3-acetyl!isonipecoticacid

The procedure of Example 35 was used except that(-)-trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepin-3-aceticacid (Example 22) was used as starting material.

64% yield

¹ H NMR identical to that of Example 35.

EXAMPLE 35B Ethyl ester of (-)-N-trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepin-3-acetyl!isonipecoticacid

A solution of 3.37 g (7.20 mmol) of(-)-trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepin-3-aceticacid in 34 mL of dry tetrahydrofuran was cooled to 0° C. and treatedwith 1.25 mL (8.11 mmol, 1.1 equivalents) of ethyl isonipecotate and 3.6mL (33 mmol, 4.6 equivalents) of 4-methylmorpholine. A 50% solution ofpropylphosphonic anhydride in ethyl acetate, 6.5 mL (11 mmol, 1.5equivalents) was added dropwise over 20 minutes. The reaction mixturewas stirred for 1.5 hours at 0° C., quenched by the dropwise addition of35 mL of water, and allowed to warm to room temperature. The layers wereseparated, the aqueous layer was washed with ethyl acetate (2×25 mL),and the combined organic phases were washed with brine, and concentratedunder vacuum to 4.44 g of a white foam. Recrystallization fromisopropanol gave 4.02 g (92% yield) of the title compound as a whitesolid.

α!_(D) -197.2° (c 0.5, methanol).

¹ H NMR (CDCl₃) δ 8.01-7.88 (m, 4H), 7.61-7.36 (m, 4H), 7.27 (dd, J=2.4,8.6 Hz, 1H), 6.76 (d, J=2.3 Hz, 1H), 6.63 (s, 1H), 4.51-4.44 (m, 1H),4.34-4.23 (m, 1H), 4.18-4.05 (m, 2H), 4.02-3.93 (m, 1H), 3.85-3.79 (m,1H), 3.40 (d, J=13.9 Hz, 1H), 3.29-3.02 (m, 2H), 2.86-2.77 (m, 1H),2.56-2.45 (m, 1H), 2.43-2.33 (m, 1H), 1.98-1.81 (m, 2H), 1.80-1.51 (m,2H), 1.27-1.17 (m, 3H), 1.09 (s, 9H).

EXAMPLE 36 Ethyl ester of N-trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepin-3-acetyl!nipecoticacid

81% yield

¹ H NMR (CDCl₃) δ 1 10 (s, 9H); 1.25 (c, 3H); 1.35-1.9 (c, 3H); 2.08 (c,1H); 2.2-3.36 (c, 6H); 3.41 (d, 1H); 3.8 (c, 1H); 3.97 (d, 1H); 4.14 (m,2H); 4.5 (c, 1H); 6.64 (s, 1H); 6.78 (s, 1H); 7.28 (d, 1H); 7.41 (t,2H); 7.5 (t, 1H); 7.60 (t, 1H); 7.9-8.05 (m, 4H).

EXAMPLE 37 Methyl ester of (-)-N-trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepin-3-acetyl!-L-proline

A procedure analogous to that of Example 35A was used.

64% yield

¹ H NMR (CDCl₃) δ 1.09 (s, 9H); 2.01 (c, 3H); 2.18 (c, 1H); 2.42 (q,1H); 3.2 (q, 1H); 3.36 (d, 1H); 3.63 (c, 2H); 3.69 (s, 3H); 4.04 (q,1H); 4.44,4.49, 4.51, 4.52 (m, 2H); 6.63 (s, 1H); 6.77 (d, 1H); 7.25 (q,1H); 7.38, 7.41, 7.43 (m, 2H); 7.49 (t, 1H); 7.61 (t, 1H); 7.91, 7.93,7.96, 7.99, 8.00, 8.03 (m, 4H).

EXAMPLE 37A γ-t-Butyl ester-α-methyl ester of N-trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepin-3-acetyl!-L-glutamicacid

Less polar diastereomer

36% yield.

¹ H NMR (250 MHz, CDCl₃) δ 1.1 (s, 9H); 1.47 (s, 9H); 1.94 (m, 1H); 2.18(m, 1H); 2.3 (c, 2H); 2.41 (q, 1H); 3.0 (q, 1H); 3.38 (d, 1H); 3.73 (s,3H); 3.92 (q, 1H); 4.47 (d, 1H); 4.55 (m, 1H); 6.45 (d, 1H);6.62 (s,1H); 6.78 (d, 1H); 7.27 (c, 1H); 7.35-7.44 (m, 2H); 7.5 (t, 1H); 7.6 (t,1H); 7.9-8.02 (m, 4H).

More polar diastereomer

34% yield.

¹ H NMR (250 MHz, CDCl₃) δ 1.1 (s, 9H); 1.42 (s, 9H); 1.95 (m, 1H); 2.15(m, 1H); 2.28 (q, 2H); 2.4 (q, 1H); 3.06 (q, 1H); 3.39 (d, 1H); 3.75 (s,3H); 3.86 (q, 1H); 4.5 (d) and 4.54 (c) (total 2H); 6.54 (d, 1H); 6.63(s, 1H); 6.77 (d, 1H); 7.28 (c, 1H); 7.4 (m 2H); 7.5 (t, 1H); 7.6 (t,1H); 7.9-8.02 (m, 4H).

EXAMPLE 37B β-t-Butylester-α-methyl ester of N-trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepin-3-acetyl!-L-asparticacid

Less polar diastereomer

14% yield.

¹ H NMR (250 MHz, CDCl₃) δ 1.1 (s, 9H); 1.46 (s, 9H); 2.46 (q, 1H); 2.69(q, 1H); 2.93 (q, 1H); 3.03 (q, 1H); 3.39 (d, 1H); 3.73 (s, 3H); 3.93(q, 1H); 4.46 (d, 1H); 4.79 (m, 1H); 6.62 (s, 1H); 6.65 (d, 1H); 6.78(d, 1H); 7.28 (c, 1H); 7.4 (m, 2H); 7.49 (t, 1H); 7.6 (t, 1H); 7.92 (d,3H); 8.0 (t, 1H).

EXAMPLE 37C Methyl ester of (-)-N-trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepin-3-acetyl!-D-proline

A procedure similar to that described in Example 36 was used.

72% yield.

¹ H NMR (250 MHz, CDCl₃) δ 1.09 (s, 9H); 1.8-2.4 (c, 5H); 2.5, 3.02,3.18 (3q, total 2H); 3.39 (q, 1H); 3.52 (c, 1H); 3.72 , 3.73 (2s, 3H);4.0 (c, 1H); 4.45 (d and c), 4.61 (c) (total 2H); 6.63 (d, 1H); 6.76(2d, 1H); 7.27 (m, 1H); 7.4 (c, 2H); 7.49 (t, 1H); 7.6 (c, 1H);7.9,.7.93, 7.95, 7.98, 8.0, 8.03 (m, 4H).

α!_(D) ²⁰ -200° (c 1.0, CHCl₃).

EXAMPLE 37D Methyl ester of (-)-N-trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepin-3-acetyl!-(R)-thiazolidine-4-carboxylicacid

A procedure similar to that described in Example 36 was used.

35% yield.

¹ H NMR (250 MHz, CDCl₃) δ 1.09 (s, 9H); 2.49 (q, 1H); 3.15-3.32 (c,3H); 3.38 (d, 1H); 3.72 (s, 3H); 4.0 (q, 1H); 4.45 (d, 1H); 4.54 (d,1H); 4.75 (d, 1H); 5.1 (m, 1H); 6.64 (s, 1H); 6.78 (d, 1H); 7.28 (c,1H); 7.40 (m, 2H); 7.5 (t, 1H); 7.61 (t, 1H); 7.9-8.02 (m, 4H).

EXAMPLE 38 N-trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl!-L-proline

A solution of 94 mg (0.68 mmol) potassium carbonate in 2 mL water wasadded to a solution of 190 mg (0.34 mmol) methyl ester of N-trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl!-L-prolinein 10 mL methanol. The resulting solution was heated at 6° C. for 3hours, cooled to room temperature and then concentrated in vacuo. Water(30 ml) was added to the residue and the mixture was acidified with 1Naqueous hydrochloric acid then extracted with 2×40 mL ethyl acetate. Thecombined ethyl acetate extracts were washed with 50 mL brine, dried overanhydrous sodium sulfate, filtered and concentrated in vacuo to yield160 mg of the title compound as an amorphous white solid (86% yield).

¹ H NMR (CDCl₃): δ 1.03, 1.05 (2s, 9H); 1.81-2.07 (c, 3H); 2.88-3.18 (m,3H); 3.38-3.79 (c, 3H); 4.5-4.65 (c and d at 4.56, total 2H); 4.68 (c,1H); 6.54 (s, 1H); 6.62 (d, 1H); 7.3-7.65 (c, 6H); 7.73-7.97 (c and d at7.93, total 3H).

The title compounds of Examples 38A through 54R were prepared by aprocedure analogous to that described in Example 38.

EXAMPLE 38A (-)-N-trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl!-L-proline

53% yield

¹ H NMR (CDCl₃) δ 1.05 (s, 9H); 2.0 (c, 3H); 2.51 (c, 1H); 2.93 (q, 1H);3.14 (q, 1H); 3.51 (d, 1H); 3.64 (c, 2H); 4.56 (d, 1H); 4.62 (c, 1H);4.69 (t, 1H); 6.54 (d, 1H); 6.63 (s, 1H); 7.32-7.56 (c, 5H); 7.61 (t,1H); 7.81 (d, 1H); 7.92 (d, 2H).

EXAMPLE 39 N-Trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl!isonipecoticacid

69% yield

¹ H NMR (CDCl₃): δ 1.04 (s, 9H); 1.5-2.0 (c, 4H); 2.57 (c, 1H); 2.88 (c,2H); 3.17 (c, 2H); 3.5 (d, 1H); 3.93 (c, 1H); 4.36 (c, 1H); 4.57 (q,1H); 4.69 (c 1H); 6.52 (s, 1H); 6.61 (s, 1H); 7.3-7.62 (c, 6H); 7.83 (t,1H); 7.91 (d, 2H).

EXAMPLE 39A (-)-N-trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl!isonipectoicacid

99% yield

1H NMR identical to that of Example 39.

α!_(D) ²⁰ -161° (methanol)

EXAMPLE 40 N-Trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl!nipecoticacid

69% yield

¹ H NMR (CDCl₃): δ 1.04 (s, 9H); 1.3-1.85 (c, 3H); 2.06 (c, 1H);2.37-3.31 (c, 6H); 3.5 (d, 1H); 3.92 (C, 2H); 4.57 (d, 1H); 4.68 (c,1H); 6.52 (s, 1H); 6.61 (s, 1H); 7.3-7.62 (c, 6H); 7.83 (d, 1H); 7.91(d, 1H).

EXAMPLE 41 N-Trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl!-L-S-methylcysteine

From the less polar ester of the title compound.

68% yield

¹ H NMR (CDCl₃): δ 1.04 (s, 9H); 1.9, 2.0 (2s, ratio 1:4, total 3H);2.78-3.07 (c, 4H); 3.48 (d 1H); 4.48-4.61 (c, 2H); 4.71 (c, 1H); 6.54(d, 1H), 6.67 (s, 1H); 7.00, 7.1 (2d, ratio 4:1, total 1H); 7.29-7.52(c, 5H); 7.59 (t, 1H); 7.82-7.95 (c, 3H).

EXAMPLE 41A (-)-N-trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl!-L-S-methylcysteine

64% yield

¹ H NMR identical to that of Example 41.

α!_(D) ²⁰ -174° (methanol).

EXAMPLE 42 N-Trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl!-L-asparticacid

91 % yield

¹ H NMR (CDCl₃) δ 0.98 (s, 9H); 2.75 (c, 2H); 3.0 (c, 2H); 3.43 (d, 1H);4.45-4.6 (c, 2H); 4.83 (c, 1H); 6.41 (d, 1H); 6.56 (s, 1H); 7.25-7.5 (c,5H); 7.54 (t, 1H); 7.75-7.9 (c, 3H).

EXAMPLE 43 N-Trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl!-L-glutamicacid

73% yield

¹ H NMR (CDCl₃) δ 1.02 (s, 9H); 2.18 (c, 2H); 2.42 (c 2H); 2.79 (c, 1H);2.98 (m, 1H); 3.46 (c, 1H); 4.49-4.65 (c, 3H); 6.52 (s, 1H); 6.60 (s,1H); 6.88, 6.98 (2d, 1H); 7.26-7.64 (c, 6H); 7.8 (m, 1H); 7.9 (m, 2H).

EXAMPLE 44 N-Trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl!-5-aminosalicylicacid

85% yield

¹ H NMR (CDCl₃) δ 0.97 (s, 9H); 2.89 (2q, 2H); 3.41 (d, 1H); 4.5 (d,1H); 4.58 (t, 1H); 6.43 (d, 1H); 6.55 (s, 1H); 6.82 (d, 1H); 7.22-7.5(c, 7H); 7.61 (q, 1H); 7.76 (d, 1H); 7.83 (q, 2H); 7.93 (d, 1H); 8.76(s, 1H); 11.02 (s, 1H).

EXAMPLE 45 N-Trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl!-4-aminosalicylicacid

80% yield

¹ H NMR (CDCl₃) δ 1.02 (s, 9H); 2.9 (q, 1H); 3.02 (q, 1H); 3.46 (d, 1H);4.55 (m, 2H); 6.5 (d, 1H); 6.61 (s, 1H); 7.01 (d, 1H); 7.21 (d, 1H);7.27-7.55 (c, 7H); 7.78 (t, 2H); 7.88 (d, 2H); 8.68 (s, 1H).

EXAMPLE 46 N-trans-7-chloro-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!nipecoticacid

75% yield.

MS (PCl): 549.

¹ H NMR (300 MHz, (CD₃)₂ SO) δ 8.31 (d, 1H), 7.92 (d, 2H), 7.66 (d, 1H),7.48 (m, 2H), 7.29 (t,1H), 7.00 (s, 2H), 6.42 (s,1H), 6.35 (s, 1H), 4.87(br d, 1H), 4.22 (br d, 1H), 3.78 (br d, 1H), 3.54 (d, 1H), 3.03 (m,1H), 2.84 (d, 1H), 2.70 (m, 1H), 2.09-1.24 (c, 6H), 1.06 (s, 9H).

EXAMPLE 47 N-trans-7-chloro-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl!isonipecoticacid

81% yield.

MS (PCl): 549.

¹ H NMR (300 MHz, (CD₃)₂ SO) δ 8.31 (d,1H), 7.92 (d, 2H), 7.65 (d, 1H),7.48 (m, 2H), 7.28 (t, 1H), 7.00 (s, 2H), 6.42 (s, 1H), 6.34 (s, 1H),4.86 (br d, 1H), 4.40 (br d, 1H), 3.72 (m, 2H), 3.54 (d, 1H), 2.84 (d,1H), 2.70-1.24 (c, 10H), 1.06 (s, 9H).

EXAMPLE 48 N-trans-7,8-trimethylene-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-acetyl!nipecoticacid

77% yield.

MS (PCl): 570 (M+H⁺).

¹ H NMR (300 MHz, (CD₃)₂ SO) δ 7.99 (t, 2H), 7.83 (t, 1H), 7.61 (m, 2H),7.49 (m, 2H), 7.38 (m, 1H), 6.45 (s, 1H), 6.21 (s, 1H), 4.36 (m, 2H),4.14 (brt, 1H), 3.86 (brs, 1H), 3.70 (d, 1H), 3.10-2.50 (c, 7H), 1.87(m, 4H), 1.48 (m, 4H), 0.98 (s, 9H).

EXAMPLE 49 N-trans-7,8-trimethylene-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-acetyl!isonipecoticacid

85% yield.

MS (PCl): 570 (M+H⁺).

¹ H NMR (300 MHz, (CD₃)₂ SO) δ 8.00 (m, 2H), 7.82 (m, 1H), 7.64 (m, 2H),7.48 (m, 2H), 7.38 (m, 1H), 6.45 (s, 1H), 6.21 (s, 1H), 4.36 (m, 2H),4.31 (d, 1H), 3.85 (m, 2H), 3.71 (d, 1H), 3.01-2.50 (c, 6H), 1.92 (m,3H), 1.60 (m, 5H), 0.98 (s, 9H).

EXAMPLE 49A N-trans-7-chloro-5-(4-methoxynaphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-acetyl!isonipecoticacid

84% yield.

MS (PCl): 593.

¹ H NMR (250 MHz, CDCl₃) δ 8.35 (d, 1H), 7.72 (t, 1H), 7.67-7.29 (m,5H), 6.89 (dd, 1H), 6.57 (d, 1H), 6.52 (s, 1H), 4.66 (m, 1H), 4.56 and4.55 (rotamers, d, 1H), 4.37 (br t, 1H), 4.05 and 4.04 (rotamers, s,3H), 3.93 (m, 1H), 3.47 (d, 1H), 3.13 (m, 2H), 2.85 (m, 2H), 2.52 (m,1H), 1.96-1.53 (m, 4H), 1.02 (s, 9H).

EXAMPLE 49B N-trans-7-chloro-5-(4-methoxynaphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-acetyl!nipecoticacid

78% yield.

MS (PCl): 593.

¹ H NMR (250 MHz, CDCl₃, major rotamer or diastereomer) δ 8.35 (d, 1H),7.70 (d, 1H), 7.48-7.29 (m, 5H), 6.90 (d, 1H), 6.57 (m, 1H), 6.52 (s,1H), 4.66 (dd, 1H), 4.55 (d, 1H), 4.05 (s, 3H), 3.93 (m, 1H), 3.47 (d,1H), 3.14-2.83 (m, 5H), 2.06 (m, 1H), 1.72-1.25 (m, 4H), 1.02 (s, 9H).

EXAMPLE 49C N-Trans-7-chloro-5-(4-methoxynaphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzothiazepine-3-acetyl!isonipecoticacid

76% yield.

MS (PCl): 610 (M+2H⁺).

¹ H NMR (300 MHz, CD₃ OD) δ 7.13 (d, 1H), 6.60 (d, 1H), 6.36 (s, 1H),4.01 (s, 3H), 0.98 (s, 9H).

EXAMPLE 49D N-Trans-7-chloro-5-(4-methoxynaphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzothiazepine-3-acetyl!-L-proline

Purification by flash column chromatography (ether) of the methyl esterof N-trans-7-chloro-5-(4-methoxynaphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzothiazepine-3-acetyl!-L-prolinegave separation of the two diastereomers.

Hydrolysis of the higher Rf diastereomer:

77% yield.

MS (PCl): 596 (M+2H⁺).

¹ H NMR (250 MHz, CDCl₃) δ 6.92 (d, 1H), 6.82 (d, 1H), 6.55 (s, 1H),4.07 (s, 3H), 1.09 (s, 9H).

Hydrolysis of the lower R_(f) diastereomer:

99% yield.

MS (PCl): 596 (M+2H⁺).

¹ H NMR (250 MHz, CDCl₃) δ 6.91 (d, 1H), 6.82 (d, 1H), 6.55 (s, 1H),4.06 (s, 3H), 1.08 (s, 9H).

EXAMPLE 49E N-Trans-7-chloro-5-(4-methoxynaphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzothiazepine-3-acetyl!-D-proline

Purification by flash column chromatography (4:1 ether/hexanes) of themethyl ester of N-trans-7-chloro-5-(4-methoxynaphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzothiazepine-3-acetyl!-D-prolinegave separation of the two diastereomers.

Hydrolysis of the higher R_(f) diastereomer:

86% yield.

¹ H NMR (250 MHz, CDCl₃) δ 6.92 (d, 1H), 6.82 (d, 1H), 6.55 (s, 1H),4.06 (s, 3H), 1.09 (s, 9H).

Hydrolysis of the lower R_(f) diastereomer:

78% yield.

¹ H NMR (250 MHz, CDCl₃) δ 6.91 (d, 1H), 6.82 (d, 1H), 6.56 (s, 1H),4.06 (s, 3H), 1.08 (s, 9H).

EXAMPLE 49F N-Trans-7-methyl-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-acetyl!isonipecoticacid

94% yield.

MS (PCl): 544 (M+2H⁺).

¹ H NMR (300 MHz, CDCl₃) δ 6.62 (s, 1H), 6.32 (s, 1H), 3.51 (d, 1H),2.00 (s, 3H), 1.03 (s, 9H).

EXAMPLE 49G N-Trans-7-methyl-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-acetyl!nipecoticacid

90% yield.

MS (PCl): 544 (M+2H⁺).

¹ H NMR (300 MHz, CDCl₃) δ 6.31 (s, 1H), 3.50 (d, 1H), 1.99 (s, 3H),1.01 (s, 9H).

EXAMPLE 49H N-Trans-7-methyl-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-acetyl!-L-proline

77% yield.

MS (PCl): 529 (M+H⁺).

¹ H NMR (250 MHz, CDCl₃) δ 6.63 (d, 1H), 6.34 (s,1H), 2.03 (s, 3H), 1.03(s, 9H).

EXAMPLE 49I N-Trans-7-methyl-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzothiazepine-3-acetyl!isonipecoticacid

93% yield.

MS (PCl): 559 (M+H⁺).

¹ H NMR (250 MHz, CDCl₃) δ 7.10 (dd, 1H), 6.66 (s, 1H), 6.58 (d, 1H),2.07 (s, 3H), 1.10 (s, 9H).

EXAMPLE 49J N-Trans-7-methyl-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzothiazepine-3-acetyl!nipecoticacid

99% yield.

MS (PCl): 559 (M+H⁺).

¹ H NMR (250 MHz, CDCl₃) δ 7.10 (d, 1H), 6.65 (s, 1H), 6.57 (s, 1H),2.07 (s, 3H), 1.10(s,9H).

EXAMPLE 49K N-Trans-7-methyl-5-(naphthalen-1-yl)-1-neorentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzothiazepine-3-acetyl!-L-proline

66% yield.

MS (PCl): 545 (M+H⁺).

¹ H NMR (250 MHz, CDCl₃) δ 6.66 (s, 1H), 6.59 (s,₁ H), 2.08 (s, 3H),1.10 (s, 9H).

EXAMPLE 49L N-Trans-7-methoxy-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-acetyl!isonipecoticacid

92% yield.

MS (PCl): 559 (M+H⁺).

1H NMR (300 MHz, CDCl₃) δ 6.86 (dd, 1H), 6.62 (s, 1H), 6.06 (t, 1H),3.44 (s, 3H), 1.03 (s, 9H).

EXAMPLE 49M N-Trans-7-methoxy-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-acetyl!nipecoticacid

98% yield.

MS (PCl): 559 (M+H⁺).

¹ H NMR (300 MHz, CDCl₃) δ 6.86 (d, 1H), 6.62 (s, 1H), 6.06 (m, 1H),3.44 (s, 3H), 1.02 (s, 9H).

EXAMPLE 49N N-Trans-7-methoxy-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-acetyl!-L-proline

74% yield.

MS (PCl): 545 (M+H⁺).

¹ H NMR (300 MHz, CDCl₃) δ 6.88 (dd, 1H), 6.63 (d, 1H), 6.07 (t, 1H),3.45 (s, 3H), 1.03 and 1.02 (2s, 9H).

EXAMPLE 49O N-Trans-7-methoxy-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzothiazepine-3-acetyl!isonipecoticacid

quantitative yield.

MS (PCl): 575 (M+H⁺).

¹ H NMR (300 MHz, CDCl₃) δ 6.81 (dd, 1H), 6.64 (s, 1H), 6.32 (d, 1H),3.53 (s, 3H), 1.09 (s, 9H).

EXAMPLE 49P N-Trans-7-acetyl-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzothiazepine-3-acetyl!isonipecoticacid

83% yield.

¹ H NMR (300 MHz, CDCl₃) δ 6.70 (s, 1H), 2.27 (s, 3H), 1.09 (s, 9H).

EXAMPLE 50 N-Trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepin-3-acetyl!-L-asparticacid

100% yield

¹ H NMR (CDCl₃): δ 1.05 (s, 9H); 2,47 (c, 1H); 2.85 (c, 1H); 3.08 (c,2H); 3.37 (d, 1H); 3.92 (c, 1H); 4.4 (d,1H); 4.85 (c, ₁ H); 6.55 (d,1H); 6.75 (s, ₁ H); 7.2-7.6 (c, 5H); 7.82-8.0 (c, 4H).

EXAMPLE 51 N-Trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepin-3-acetyl!-L-glutamicacid

96% yield

¹ H NMR (CDCl₃) δ 1.08 (s, 9H); 2.2 (c, 2H); 2.4-2.56 (c, 3H); 3.06 (c,1H); 3.38(q, 1H); 3.91 (m, 1H); 4.46 (q, 1H); 4.6 (c, 1H); 6.59 (s, 1H);6.77 (s, 1H); 6.9, 7.07 (2d, 1H); 7.24-7.62 (c, 5H); 7.86-8.0 (c, 4H).

EXAMPLE 52 N-Trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepin-3-acetyl!isonipecoticacid

93% yield

¹ H NMR (CDCl₃) δ 1.10(s, 9H); 1.5-2.05 (c, 4H); 2.38 (d, 1H); 2.58 (c,1H); 2.87 (c, 1H); 3.05-3.32 (c, 2H); 3.41 (d, 1H); 3.85 (c, ₁ H); 3.98(d, 1H); 4.3 (c, 1H); 4.49 (2d, 1H); 6.64 (s, 1H); 6.77 (d, 1H); 7.3 (d,1H); 7.41 (t, 2H); 7.5 (t, 1H); 7.6 (t, 1H); 7.91, 7.93, 7.96, 8.0, 8.02(m, 4H).

EXAMPLE 52A N-(-)-trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepin-3-acetyl!isonipecoticacid

97% yield

¹ H NMR identical to that of Example 52.

α!_(D) ²⁰ -189° (methanol)

EXAMPLE 53 N-Trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepin-3-acetyl!nipecoticacid

84% yield

¹ H NMR (CDCl₃) δ 1.1(s, 9H); 1.35-1.92 (C, 3H); 2.1 (c, 1H); 2.32-3.35(c, 6H); 3.41 (d, 1H); 3.8 (c, 1H); 3.98 (d, 1H); 4.48 (d, 1H); 6.64 (s,1H); 6.77 (s, 1H); 7.28 (d, 1H); 7.4 (c, 2H); 7.5 (t, 1H); 7.6 (t, 1H);7.88-8.06 (c, 4H).

EXAMPLE 54 N-(-)-trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepin-3-acetyl!-L-proline

97% yield

¹ H NMR (CDCl₃) δ 1.10(s, 9H); 2.04 (c, 3H); 2.3-2.5 (c, 2H); 3.2 (q,1H); 3.41 (d, 1H); 3.6 (c, 2H); 4.0 (d, 1H); 4.46 (d, 1H); 4.57 (d, 1H);6.64 (s, 1H); 6.79 (d, 1H); 7.3 (q, 1H); 7.41 (q, 2H); 7.50 (t, 1H);7.61 (t, 1H); 7.92, 7.94, 7.99, 8.02 (m, 4H).

EXAMPLE 54ATrans-7-methylthio-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-aceticacid

94% yield.

¹ H NMR (250 MHz, CDCl₃) δ 1.04 (s, 9H), 2.07 (s, 3H); 2.93 (q, 1H);3.12 (q, 1H); 3.5 (d, 1H); 4.52 (c) and 4.57 (d) (total 2H); 6.4 (d,1H); 6.63 (s, 1H); 7.24 (m, 1H); 7.32 (m, 2H); 7.47 (m, 2H); 7.58 (t,1H); 7.84 (d, 1H); 7.89 (d, 2H).

EXAMPLE 54BTrans-7-trifluoromethoxy-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-aceticacid

97% yield.

¹ H NMR (250 MHz, CDCl₃) δ 1.04 (s, 9H); 2.94 (q, 1H); 3.17 (q, 1H);3.52 (d, 1H); 4.52 (q, 1H); 4.6 (d, 1H); 6.39 (d, 1H); 6.63 (s, 1H);7.25 (c, 1H); 7.31 (t, 1H); 7.47 (q, 3H); 7.59 (t, 1H); 7.85 (d, 1H);7.92 (d, 2H).

EXAMPLE 54CTrans-7,8-ethylenedioxy-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-aceticacid

49% yield.

¹ H NMR (250 MHz, CDCl₃) δ 1.06 (s, 9H); 2.93 (q, 1H); 3.1 (q, 1H); 3.4(d, 1H); 4.12 (c, 2H); 4.2 (c, 2H); 4.5 (c, 1H); 4.55 (c, 1H); 6.05 (s,1H); 6.59 (s, 1H); 6.94 (s, 1H); 7.32 (m, 1H); 7.44 (t, 1H); 7.56 (t,2H); 7.86 (q, 3H).

EXAMPLE54DTrans-7-trifluoromethyl-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-aceticacid

85% yield.

¹ H NMR (250 MHz, CDCl₃) δ 1.05 (s, 9H); 2.94 (q, 1H); 3.18 (q, 1H);3.59 (d, 1H); 4.5 (q, 1H); 4.62 (d, 1H); 6.67 (s, 1H); 6.84 (s, 1H);7.31 (t, 1H); 7.45 (2d, 2H); 7.62 (m, 3H); 7.87 (d, 1H); 7.93 (d, 2H).

EXAMPLE 54E

N-Trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl!-1-amino-1-cyclopentanecarboxylicacid

58% yield.

¹ H NMR (250 MHz, DMSO-d₆) δ 0.96 (s, 9H); 1.66 (c, 4H); 1.93 (c, 4H);2.56, 2.68 (2q, 2H); 3.43 (m, 1H); 3.71 (d, 1H); 4.38 (c, 2H); 6.23 (d,1H); 6.45 (s, 1H); 7.4 (c, 2H); 7.48-7.64 (c, 3H); 7.82 (d, 2H); 8.02(c, 2H).

EXAMPLE 54F N-Trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl-1-amino-1-cyclopropanecarboxylicacid

12% yield.

¹ H NMR (250 MHz, CDCl₃) δ 1.03 (s, 9H); 1.22 (c, 2H); 1.6 (c, 2H); 2.73(q, 1H); 2.95 (q, 1H); 3.47 (d, 1H); 4.54 (c, 2H); 6.52 (d, 1H); 6.61(s, 1H); 6.67 (s, 1H); 7.36 (c, 3H); 7.47 (t, 2H); 7.59 (t, 1H); 7.85(d, 1H); 7.92 (d, 2H).

EXAMPLE 54G (-)-N-Trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl!-L-methioninre

55% yield.

¹ H NMR (250 MHz, CDCl₃) δ 1.04 (s, 9H); 1.92-2.28 (c, 5H); 2.54 (c,2H); 2.81 (q, 1H); 2.97 (q, 1H); 3.48 (d, 1H); 4.54 (m, 2H); 4.66 (m,1H); 6.53 (d, 1H); 6.62 (s, 1H); 6.69 (d, 1H); 7.3-7.41 (c, 3H); 7.46(t, 2H); 7.59 (t, 1H); 7.84 (d, 1H); 7.91 (d, 2H);

α!_(D) ²¹ -158.4° (c 1.0, MeOH).

EXAMPLE 54H N-Trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl!-cis-4-hydroxy-D-proline

79% yield.

¹ H NMR (250 MHz, CDCl₃) δ 1.02, 1.04 (2s, 9H); 1.95-2.3 (c, 1H); 2.5(q, 1H); 2.9 (q, 1H); 3.14 (q, 1H); 3.47 (d, 1H), 3.56-3.82 (c, 2H);4.13 (m, 1H); 4.54 (q, 1H); 4.67 (t, 2H); 6.54 (t, 1H); 6.61 (d, 1H);7.3-7.64 (c, 6H); 7.7 (d), 7.84 (d) (total 1H); 7.92 (d, 2H).

EXAMPLE 54I N-Trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl!-trans-4-hydroxy-L-proline

80% yield.

¹ H NMR (250 MHz, CDCl₃ 6 1.03 (s, 9H); 2.24 (c, 1H); 2.5 (c, 1H); 2.88(q, 1H); 3.0 (c, 1H); 3.18 (q, 1H); 3.49 (d, 2H); 4.5 (c, 2H); 4.7 (c,2H); 6.54 (s, 1H); 6.62 (s, 1H); 7.3-7.64 (c, 6H); 7.81 (t, 1H); 7.92(d, 2H).

EXAMPLE 54J N-Trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl!-4-azetidinecarboxylicacid

86% yield.

¹ H NMR (250 MHz, CDCl3) δ 1.03, 1.04 (2s, 9H); 2.62 (q), 2.7 (c), 2.8(q) (total 3H); 3.47 (d, 1H); 4.04.68 (c, 6H); 6.51 (s, 1H); 6.61 (s,1H); 7.35 (c, 3H); 7.4-7.64 (c, 3H); 7.8 (q, 1H); 7.9 (c, 2H).

EXAMPLE 54K N-Trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl!-D-proline

96% yield.

¹ H NMR (250 MHz, CDCl₃) δ 1.04 (s, 9H); 1.8-2.1 (c, 3H); 2.46 (c, 1H);3.0 (m, 2H); 3.44-3.6 (c and d at 3.49, 2H); 3.75 (c, 1H); 4.56 (d) and4.6 (c) (total 2H); 4.7 (t, 1H); 6.54 (d, 1H); 6.61 (s, 1H); 7.32-7.6(c, 6H); 7.76 (d, 1H); 7.93 (d, 2H).

EXAMPLE 54L (-)-N-Trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl!-L-pipecolinicacid

81% yield.

¹ H NMR (250 MHz, CDCl₃) δ 1.04 (s, 9H); 1.4-1.8 (c, 5H); 2.25 (c, 1H);2.86 (q, 1H); 3.2 (m, 1H); 3.32 (q, 1H); 3.51 (d, 1H); 3.9 (c, 1H); 4.57(d, 1H); 4.68 (q, 1H); 5.28 (c, 1H); 6.52 (d, 1H); 6.62 (s, 1H);7.3-7.65 (c, 6H); 7.9 (c, 3H).

α!_(D) ²⁰ -195.6° (c 0.91, CHCl₃).

EXAMPLE 54M (-)-N-Trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl!-(-)-nipecoticacid

62% yield.

¹ H NMR (250 MHz, CDCl₃) identical to that of Example 40.

EXAMPLE 54N N-Trans-7-trifluoromethyl-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl!nipecoticacid

78% yield.

¹ H NMR (250 MHz, CDCl₃) δ 1.04 (s, 9H); 1.5-1.85 (c, 3H); 2.05 (c, 1H);2.4-3.5 (c, 6H); 3.58 (d, 1H); 3.9 (c, 1H); 4.6 (d, 1H); 4.66 (c, 1H);6.65 (s, 1H); 6.81 (d, 1H); 7.32 (c, 1H); 7.46 (t, 2H); 7.6 (s and c,3H); 7.86 (t, 1H); 7.92 (d, 2H).

EXAMPLE 54O N-Trans-7-trifluoromethyl-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl!isonipecoticacid

84% yield.

¹ H NMR (250 MHz, CDCl₃) δ 1.04 (s, 9H); 1.46-2.0 (c, 4H); 2.56 (c, 1H);2.87 (c, 2H); 3.17 (c, 2H); 3.58 (d, 1H); 3.92 (c, 1H); 4.34 (c, 1H);4.6 (2d, 1H); 4.66 (c, 1H); 6.65 (s, 1H); 6.82 (s, 1H); 7.32 (t, 1H);7.48 (c, 2H); 7.6 (s and c, 3H); 7.85 (t, 1H); 7.92 (d, 2H).

EXAMPLE 54P N-Trans-7-trifluoromethyl-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl!-L-proline

80% yield.

¹ H NMR (250 MHz, CDCl₃) δ 1.04,1.05 (2s, 9H); 1.8-2.1 (c, 3H);2.86-3.23 (m, 3H); 3.4-3.8 (c, 3H); 4.59 (d and c, 2H); 4.69 (c, 1H);6.66 (d, 1H); 6.84 (s, 1H); 7.34 (c, 1H); 7.48 (c, 2H); 7.62 (c, 3H);7.8 (q, 1H); 7.93 (d, 2H).

EXAMPLE 54Q (-)-N-Trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepin-3-acetyl!-D-proline

99% yield.

¹ H NMR (250 MHz, CDCl₃) δ 1.1 (s, 9H); 2.03 (c, 3H); 2.42-2.56 (c, 2H);3.22 (q, 1H); 3.4-3.6 (c and d at 3.42, 2H); 3.82 (c, 1H); 4.0 (q, 1H);4.43 (d, 1H); 4.56 (d, 1H); 6.64 (s, 1H); 6.79 (d, 1H); 7.3 (q, 1H);7.41 (q, 2H); 7.51 (t, 1H); 7.6 (t, 1H); 7.92, 7.94, 7.97, 7.98 and 8.0(m, 4H);

EXAMPLE 54R (-)-N-Trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepin-3-acetyl!-(R)-thiazolidine-carboxylicacid

78% yield.

¹ H NMR (250 MHz, CDCl₃) δ 1.1 (s, 9H); 2.5 (q, 1H); 3.2-3.5 (c, 4H);4.0 (q, 1H); 4.45 (d, 1H); 4.51 (d, 1H); 4.75 (d, 1H); 5.04 (c, 1H);6.64 (s, 1H); 6.79 (d, 1H); 7.3 (c, 1H); 7.38 (m, 2H); 7.5 (t, 1H); 7.61(t, 1H); 7.9-8.02 (m,4H).

EXAMPLE 55 (-)-N-trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl!-L-asparticacid-α-methyl ester

Trifluoroacetic acid (1.5 ml) was added to a solution of 68 mg (0.1mmol) of the less polar diastereomer of β-t-butyl ester-α-methyl esterof N-trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl!-L-asparticacid in 1.5 mL dichloromethane at room temperature. The resultingsolution was stirred at room temperature for 3 hours, then concentratedin vacuo. The residue was triturated 4× with hexane and filtered toyield 41 mg (71 % yield) of the title compound as a white solid.

¹ H NMR (CDCl₃) δ 1.02 (s, 9H); 2.82 (c, 2H); 3.07 (c, 3H); 3.47 (d,1H); 3.67 (s, 3H); 4.55 (c, 2H); 4.86 (c, 1H); 6.53 (d, 1H); 6.59 (s,1H); 7.29-7.5 (c, 5H); 7.6 (t, 1H); 7.86 (d, 1H); 7.92 (d, 2H).

EXAMPLE 56 (+)-N-trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl!-L-asparticacid-α-methyl ester

Following a procedure analogous to that described in Example 55 butusing the more polar diastereomer as starting material, the titlecompound was obtained as white solid in 82% yield.

¹ H NMR (CDCl₃) δ 1.03 (s, 9H); 2.81 (c, 2H); 3.0 (c, 2H); 3.48 (d, 1H);3.72 (s, 3H): 4.54 (c, 2H); 4.81 (c, 1H); 6.52 (d, 1H); 6.6 (s, 1H);7.27-7.51 (c, 5H); 7.58 (t, 1H); 7.81 (d, 1H); 7.9 (d, 2H).

EXAMPLE 57 (-)-N-trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl!-L-glutamicacid-α-methyl ester

Following a procedure analogous to that described in Example 55 butusing the less polar diastereomer of γ-t-butyl ester-α-methyl ester ofN-trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl!-L-glutamicacid, the title compound was obtained as a white solid in 88% yield.

¹ H NMR (CDCl₃) δ 1.03 (s, 9H); 1.97 (m, 1H); 2.24 (c, 1H); 2.44 (c,2H); 2.8 (q, 1H); 2.98 (q, 1H); 3.48 (d, 1H); 3.69 (s, 3H); 4.59 (c,3H); 6.52 (d, 1H); 6.60 (s, 1H); 6.74 (d, 1H); 7.3-7.5 (c, 5H); 7.59 (t,1H); 7.84 (d, 1H); 7.91 (d, 2H).

EXAMPLE 58 (+)-N-trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl!-L-glutamicacid-a methyl ester

Following a procedure analogous to that described in Example 55 butusing the more polar diastereomer of y-t-butyl ester-α-methyl ester ofN-trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl!-L-glutamicacid, the title compound was obtained as a white solid in 96% yield.

¹ H NMR (CDCl₃) δ 1.03 (s, 9H); 1.93 (m, 1H); 2.18 (m, 1H); 2.36 (c,2H); 2.82 (q, 1H); 2.98 (q, 1H); 3.48 (d, 1H); 3.72 (s, 3H); 4.58 (c,3H); 6.53 (d, 1H); 6.62 (s, 1H); 7.01 (d, 1H); 7.3-7.52 (c, 5H); 7.59(t, 1H); 7.83 (d, 1H); 7.90 (d, 2H).

EXAMPLE 58A (-)-N-Trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepin-3-acetyl!-L-glutamicacid-α-methyl ester

A procedure similar that described in Example 55 was used using the lesspolar diastereomer from Example 37A.

78% yield.

¹ H NMR (250 MHz, CDCl₃) δ 1.09 (s, 9H); 1.97 (c, 1H); 2.28 (c, 1H);,2.48 (c, 3H); 3.0 (q, 1H); 3.38 (d, 1H); 3.74 (s, 3H); 3.96 (c, 1H);4.45 (d, 1H); 4.6 (c, 1H); 6.6 (s, 1H); 6.65 (d, 1H); 6.78 (d, 1H);7.28(c, 1H); 7.39 (m, 2H); 7.5 (t, 1H); 7.59 (t, 1H); 7.88-8.0 (c, 4H);

α!_(D) ²⁰ -190° (c 1.0, CHCl₃).

EXAMPLE 58B (+)-N-Trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepin-3-acetyl!-L-glutamicacid-α-methyl ester

A procedure similar to that described in Example 56 was used using themore polar diastereomer from Example 37A.

75% yield.

¹ H NMR (250 MHz, CDCl₃) δ 1.09 (s, 9H); 2.0 (c, 1H); 2.2 (c, 1H); 2.46(c, 3H); 3.07 (q, 1H); 3.39 (d, 1H); 3.75 (s, 3H); 3.87 (c, 1H); 4.47(d, 1H); 4.58 (c, 1H); 6.61 (s, 1H); 6.77 (d, 1H); 6.94 (d, 1H); 7.27(c, 1H); 7.3-7.45 (m, 2H); 7.49 (t, 1H); 7.58 (t, 1H); 7.88-8.02 (c,4H).

α!_(D) ²⁰ -184.70 (c 1.0, CHCl₃).

EXAMPLE 58C (-)-N-Trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepin-3-acetyl!-L-asparticacid-α-methyl ester

A procedure similar that described in Example 55 was used using Example37B as starting material.

69% yield.

¹ H NMR (250 MHz, CDCl₃) δ 1.1 (s, 9H); 2.48 (q, 1H); 2.8 (q, 1H); 3.13(c, 2H); 3.4 (d, 1H); 3.73 (s, 3H); 4.04 (q, 1H); 4.42 (d, 1H); 4.87 (c,1H); 6.58 (s, 1H); 6.8 (d, 1H); 7.25-7.47 (c, 3H); 7.5 (t, 1H); 7.6 (t,1H); 7.92 (d, 3H); 7.99 (t, 1H).

EXAMPLE 59 Methyl ester of N-trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl!-5-aminosalicylicacid

To a mixture of 129 mg (0.51 mmol) 2-chloro-1-methylpyridinium iodide in10 mL dichloromethane was added 208 mg (0.46 mmol)trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-aceticacid, 92 mg (0.55 mmol) methyl 5-amino salicylate and 0.064 mL (0.46mmol) triethylamine. The reaction mixture was refluxed under nitrogenfor 7 hr and the resulting solution was cooled to room temperature andconcentrated in vacuo. The residue was partitioned between 20 mL waterand 60 mL ethyl acetate and the ethyl acetate layer was washed with 25mL 1N aqueous hydrochloric acid, 25 mL water and 25 mL brine. The ethylacetate solution was dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo. The residue was chromatographed on 100 g silicagel, eluting with 3:2 hexane/ethyl acetate to yield 132 mg (49% yield)of the title compound as a white solid.

¹ NMR (CDCl₃): δ 1.05 (s, 9H); 2.9 (q, 1H); 3.03 (q, 1H); 3.48 (d, 1H);3.94 (s, 3H), 4.55, 4.58, 4.6, 4.62 (2d, 2H); 6.53 (d, 1H); 6.65 (s,1H); 6.94 (d, 1H); 7.38-7.58 (c, 7H); 7.73 (s, 1H); 7.82 (d, 1H); 7.92(d, 2H); 8.04 (d, 1H).

EXAMPLE 60 Methyl ester of N-trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl14-aminosalicylicacid

Using a procedure analogous to that described in Example 59 except thatmethyl 4-amino salicylate was used as starting material, the titlecompound was obtained as a white solid in 36% yield.

¹ H NMR (CDCl₃) δ 1.05 (s, 9H); 2.91 (q, 1H); 3.06 (q, 1H); 3.48 (d,1H); 3.93 (s, 3H); 4.58 (c, 2H); 6.54 (s, 1H); 6.65 (s, 1H); 7.03 (d,1H); 7.18 (d, 1H); 7.3-7.64 (c, 6H); 7.75, 7.78, 7.81, 7.83 (m, 2H);7.92 (d, 2H); 8.06 (s, 1H); 10.82 (s, 1H).

EXAMPLE 61N-(Trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepin-3-acetyl)methanesulfonamide

To a stirred solution of 190 mg (0.41 mmol)trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepin-3-aceticacid in 10 mL dichloromethane at room temperature was added 49 mg (0.52mmol) methane sulfonamide, 63 mg (0.52 mmol) 4-dimethylaminopyridine and213 mg (0.518 mmol) 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimidemetho-p-toluenesulfonate and the reaction mixture was stirred at roomtemperature overnight. Dichloromethane (20 ml) was added and theresulting solution was washed with 15 mL of 2N aqueous hydrochloricacid, dried over anhydrous sodium sulfate, filtered and concentrated invacuo. The residue (200 mg) was chromatographed on 100 g silica gel,eluting with 9:1 ethyl acetate/methanol to yield 81 mg (37% yield) ofthe title compound as a white solid.

¹ H NMR (CDCl₃) δ 1.08 (s, 9H); 2.6 (m, 1H); 3.02 (t, 1H); 3.2 (s, 3H);3.4 (d, 1H); 3.91 (m, 1H); 4.5 (d, 1H); 6.6 (s, 1H); 6.78 (d, 1H);7.25-7.61 (m, 5H); 7.91 (m, 4H).

EXAMPLE 62 N-trans-7-chloro-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-acetyl!methylsulfonamide

The title compound was prepared in a manner analogous to that describedin example 61 except 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride was used as the carbodiimide.

68% yield.

MS (PCl): 547 (M+NH₄ ⁺).

¹ H NMR (250 MHz, (CD₃)₂ SO) δ 8.05 (d, 2H), 7.84 (m, 2H), 7.68-7.43 (m,5H), 6.46 (s, 1H), 6.27 (d, 1H), 4.47 (t, 1H), 4.35 (d, 1H), 3.75 (d,1H), 3.22 (s, 3H), 2.86 (d, 2H), 0.97 (s, 9H).

EXAMPLE 63Trans-7-chloro-5-(naphthalen-1-yl)-1-neopentyl-3-(1H-tetrazol-5-ylmethyl)-1,2,3,5-tetrahydro-4,1-benzothiazepin-2-oneEXAMPLE 63ATrans-7-chloro-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzothiazepine-3-acetamide

A solution oftrans-7-chloro-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzothiazepine-3-aceticacid (200 mg, 426 μmol), 1,1'-carbonyidiimidazole (143 mg, 853 μmol) andtetrahydrofuran (5 mL) was heated at reflux for 1.5 hours. The resultingreaction mixture was cooled to 0° C. and a solution of tetrahydrofuransaturated with anhydrous ammonia (5 mL) was added. After 0.5 hours thereaction mixture was warmed to ambient temperature, concentrated underreduced pressure and purified by flash column chromatography (1:1hexanes/ethyl acetate) to provide 200 mg (quantitative) of the titlecompound as a white powder.

MS (PCl): 467 (M+H⁺).

¹ H NMR (300 MHz, CDCl₃) δ 7.96 (m, 4H), 7.60 (t, 1H), 7.52-7.29 (m,4H), 6.79 (d, 1H), 6.62 (s, 1H), 5.80 (br s, 1H), 5.34 (br s, 1H), 4.48(d, 1H), 3.94 (dd, 1H), 3.39 (d, 1H), 2.98 (dd, 1H), 2.40 (dd, 1H), 1.10(s, 9H).

EXAMPLE 63BTrans-7-chloro-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzothiazepine-3-acetonitrile

Trifluoroacetic anhydride (441 mg, 210 mmol, 296 μL) was added to asolution oftrans-7-chloro-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzothiazepine-3-acetamide(98 mg, 210μmol) and pyridine (2.1 mL) at 0° C. After 1.5 h, thereaction mixture was diluted with ether, washed with water (2×) and 0.5N aqueous hydrochloric acid, dried over anhydrous sodium sulfate,concentrated under reduced pressure and purified by flash columnchromatography (methylene chloride) to give 88 mg (93%) of the titlecompound as a white solid.

MS (PCl): 449 (M+H⁺).

¹ H NMR (250 MHz, CDCl₃) δ 7.98 (m, 4H), 7.64-7.26 (m, 5H), 6.83 (s,1H), 6.07 (s, 1H), 4.52 (d, 1H), 3.72 (t, 1H), 3.40 (d, 1H), 3.03 (dd,1H), 2.71 (dd, 1H), 1.12 (s, 9H).

EXAMPLE 63CTrans-7-chloro-5-(naphthalen-1-yl)-1-neopentyl-3-(1H-tetrazol-5-ylmethyl)-1,2,3,5-tetrahydro-4,1-benzothiazepin-2-one

A heterogeneous mixture oftrans-7-chloro-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzothiazepine-3-acetonitrile(75 mg, 167 μmol), trimethyltin azide (70 mg, 334 μmol) and toluene (2mL) was heated at reflux for 18 hours. Reaction mixture concentratedunder reduced pressure and purified by flash column chromatography(80:15:1 chloroform/methanol/ammonium hydroxide) to yield a clear oilwhich was taken up in ethyl acetate, washed with 0.5 N hydrochloricacid, dried over anhydrous sodium sulfate and concentrated under reducedpressure to provide 58.5 mg (71 %) of the title compound as a whitepowder.

MS (PCl): 492 (M+H⁺).

¹ H NMR (250 MHz, CDCl₃) δ 7.93 (m, 4H), 7.61-7.29 (m, SH), 6.81 (s,1H), 6.60 (s, 1H), 4.48 (d, 1H), 3.98 (dd, 1H), 3.64 (dd, 1H), 3.34 (m,2H), 1.10 (s, 9H).

EXAMPLE 64 Trans-7-chloro-5-(naphthalen-1-yl)-1-neopentyl-3-{2-oxo-2-4-(1H-tetrazol-5-yl)-piperidin-1-yl!-ethyl}-1,2,3,5-tetrahydro-4,1-benzothiazepin-2-one

Prepared as described in example 63. From N-trans-7-chloro-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzothiazepine-3-acetyl!isonipecoticacid.

60% yield.

¹ H NMR (250 MHz, DMSO-d₆) δ 6.58 (d, 1H), 6.49 (s, 1H), 1.02 (s, 9H).

EXAMPLE 65 4'-Trifluoromethyl-2,2-dimethylpropionanilide

To a stirred solution of 4-trifluoromethylaniline (25 g, 0.155 mol) andpyridine (62 ml, 0.775 mol) in dichloromethane (300 ml) cooled to 0° C.under nitrogen was added dropwise pivaloyl chloride (19 ml, 0.155 mol).The reaction mixture was stirred at room temperature for 3.5 hr, thendiluted with dichloromethane (300 ml). The resulting solution was washedsequentially with 1N aqueous hydrochloric acid solution (2×), saturatedaqueous sodium bicarbonate solution, water and brine, dried (anhydroussodium sulfate)and concentrated in vacuo to yield the title compound asa white solid (37 g, 97% yield).

¹ H NMR (250 MHz, CDCl₃) δ 1.33 (s, 9H); 7.74 (b, 1H); 7.57 (d, 2H);7.67 (d, 2H).

EXAMPLE 66 2'-α-Hydroxy-(1-naphthyl)methyl!-4'-trifluoromethyl-2,2-dimethylpropionanilide

To a stirred solution of 4'-trifluoromethyl-2,2-dimethylpropionanilide(37 g, 0.15 mol) in anhydrous tetrahydrofuran (400 ml) cooled to 0° C.under nitrogen was added slowly a solution of n-butyllithium (160 mL of2.5M solution in hexane, 0.4 mol). The reaction mixture was stirred at0° C. for 2 hr, then a solution of 1-naphthaldehyde (40.7 ml, 0.3 mol)in tetrahydrofuran (50 ml) was slowly added. The resulting solution wasstirred at room temperature overnight, quenched with water, diluted withethyl acetate and separated. The aqueous phase was extracted with ethylacetate (2×) and the combined ethyl acetate extracts were washed withwater and brine, dried (anhydrous sodium sulfate) and concentrated. invacuo to an oil (74 g). The crude product was chromatographed on 2 kgsilica gel, eluting with 8:2 hexane/ethyl acetate to yield the titlecompound as a tan solid (31 g, 52% yield).

¹ H NMR (250 MHz, CDCl₃) δ 1.12 (s, 9H); 3.05 (d, 1H); 6.65 (d, 1H);7.33 (d, 1H); 7.45 (t, 1H); 7.56 (c, 3H); 7.92 (c, 2H); 8.04 (q, 1H);8.4 (d, 1H); 9.11 (b, 1H).

EXAMPLE 672-Neopentylamino)-5-trifluoromethylphenyl!-(1-naphthyl)methanol

To a stirred solution of 2-α-hydroxy-(1-naphthyl)methyl!4-trifluoromethyl-2,2-dimethylpropioanilide(5 g, 12.5 mmol) in anhydrous tetrahydrofuran (50 ml) under nitrogen wasslowly added borane-tetrahydrofuran complex (12.5 mL of a 1.0M solutionin tetrahydrofuran, 12.5 mmol). The reaction mixture was stirred at roomtemperature for 1 hr, then heated at reflux for 1.5 hr. Additionalborane-tetrahydrofuran complex (12.5 mL of a 1.0M solution intetrahydrofuran, 12.5 mmol) was added at room temperature and theresulting solution was heated at reflux for 1 hr. The reaction mixturewas then cooled to room temperature, 2 mL methanol was added and after 5minutes the solution was acidified with 2N aqueous hydrochloric acidsolution. After 10 minutes the solution was basified with aqueousammonium hydroxide solution, diluted with water and extracted with ethylacetate (3×). The ethyl acetate extracts were washed sequentially withwater and brine, dried (anhydrous sodium sulfate) and concentrated invacuo to an oil. The crude product was chromatographed on silica gel,eluting with 85:15 hexane/ethyl acetate to yield the title compound as awhite solid (2.4 g, 50% yield).

¹ H NMR (250 MHz, CDCl₃) δ 0.81 (S, 9H); 2.36 (d, 1H); 2.89 (d, 2H);4.81 (b, 1H); 6.56 (d, 1H); 6.72 (d,1H); 7.29 (d, 1H); 7.42-7.57 (c,5H); 7.9 (c, 2H), 8.08 (m, 1H).

It should be understood that the invention is not limited to theparticular embodiments shown and described herein, but that variouschanges and modifications may be made without departing from the spiritand scope of this novel concept as defined by the following claims.

We claim:
 1. A compound of Formula I ##STR18## and the pharmaceuticallyacceptable cationic and anionic salts, prodrugs and stereoisomersthereofwherein X is oxy, thio,--S(O)-- or --S(O)₂ --; Y is carbonyl ormethylene; R₁, R₂, R₃ and R₉ are each independently hydrogen, halo,hydroxyl, trifluoromethyl, (C₁ -C₄)alkyl, fluorinated (C₁ -C₄)alkylhaving from 1 to 9 fluorines, (C₁ -C₄)alkoxy, fluorinated (C₁ -C₄)alkoxyhaving from 1 to 9 fluorines, (C₁ -C₄)alkylthio, (C₁ -C₄)alkylsulfinyl,(C₁ -C₄)alkylsulfonyl, phenyl, amino, morio-N- or di-N,N-(C₁-C₄)alkylamino, carboxyl, (C₁ -C₄)alkoxycarbonyl, carbamoyl, mono-N- ordi-N,N-(C₁ -C₄)alkylcarbamoyl, (C₁ -C₄)alkanoylamino, fluorinated (C₁-C₄)alkanoylamino having from 1 to 9 fluorines, (C₁-C₄)alkylsulfonylamino or fluorinated (C₁ -C₄)alkylsulfonylamino havingfrom 1 to 9 fluorines, (C₁ -C₆)alkanoyl, (C₁ -C₆)alkanoyl(C₁ -C₆)alkyl,oxazolyl, thiazolyl, isoxazolyl, pyrazolyl or isothiazolyl wherein saidpreceding heterocycles are carbon linked and wherein R₁ and R₂ can betaken together to form a five, six or seven membered carbocyclic ring orcan be taken together to form methylenedioxyl, ethylenedioxyl orpropylenedioxyl and such rings formed by taking R₁ and R₂ together arefused at the 7 and 8 positions; R₄ is (C₁ -C₇)alkyl or (C₃-C₄)cycloalkylmethyl; Z is carboxyl, (C₁ -C₄)alkoxycarbonyl,aminocarbonyl, cyano, hydroxyarninocarbonyl, --C(O)N(H)SO₂ R₅,tetrazol-5-yl, 4,5-dihydro-5-oxo-1,2,4-oxadiazol-3yl,tetrazol-5-yl-aminocarbonyl, 3-oxoisoxazolidin-4-yl-aminocarbonyl,##STR19## R₅ is amino or mono-N- or di-N,N-(C₁ -C₄)alkylamino; (C₁-C₄)alkyl optionally substituted with 1 to 9 fluorines, amino, mono-N-or di-N,N-(C₁ -C₄)alkylamino, carboxyl, (C₁ -C₄)alkoxycarbonyl,carbamoyl or mono-N- or di-N,N-(C₁ -C₄)alkylcarbamoyl; phenyl optionallymono- or di-substituted independently with methyl, methoxyl, fluoro,trifluoromethoxyl, carboxyl, (C₁ -C₄)alkoxycarbonyl, methylthio,methylsulfinyl, methylsulfonyl, (C₁ -C₄)alkylsulfonylamino or mono-N- ordi-N,N-(C₁ -C₄)alkylaminosulfonyl; or thiazolyl, isothiazolyl, thienyl,furyl, pyridinyl or such heterocycles optionally mono-substituted bycarboxyl, or mono- or di-substituted with methyl; R₆ is hydrogen,hydroxyl or methoxyl; T forms a five to seven membered mono-aza,saturated ring, said ring optionally containing thia and said ringoptionally mono-substituted on carbon with hydroxyl; U forms a three toseven membered saturated carbocyclic ring; V is --CO₂ R₇, aminocarbonyl,cyano, tetrazol-5-yl, 4,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl,tetrazol-5-yl-aminocarbonyl or 3-oxoisoxazolidin-4-yl-aminocarbonyl; R₇is hydrogen or (C₁ -C₄)alkyl; p is 1, 2, 3 or 4; R₈ is hydroxyl, thiol,carboxyl, (C₁ -C₄)alkoxycarbonyl, carbamoyl, amino, sulfamoyl, (C₁-C₄)alkoxy, fluorinated (C₁ -C₄)alkoxy having from 1 to 9 fluorines, (C₁-C₄)alkylthio, (C₁ -C₄)alkylsulfonyl, (C₁ -C₄)alkylsulfinyl, mono-N- ordi-N,N-(C₁ -C₄)alkylcarbamoyl, mono-N- or di-N,N-(C₁ -C₄)alkylamino, (C₁-C₄)alkylsulfonylamino, fluorinated (C₁ -C₄)alkylsulfonylamino havingfrom 1 to 9 fluorines, (C₁ -C₄)alkanoylamino, fluorinated (C₁-C₄)alkanoylamino having from 1 to 9 fluorines, mono-N- or di-N,N-(C₁-C₄)alkylaminosulfonyl, ureido, mono-N- or di-N,N-(C₁ -C₄)ureido,imidazolyl or pyridyl; and W is pyridyl, pyrimidyl, 1,3,4-oxadiazolyl,1,3,4-thiadiazolyl, thiazolyl, 1,3,4-triazolyl or oxazolyl.
 2. Acompound as recited in claim 1 whereinR₁, R₂, R₃ and R₉ are eachindependently hydrogen, halo, hydroxyl, trifluoromethyl, (C₁ -C₄)alkyl,fluorinated (C₁ -C₄)alkyl having from 1 to 9 fluorines, (C₁ -C₄)alkoxy,fluorinated (C₁ -C₄)alkoxy having from 1 to 9 fluorines, (C₁-C₄)alkylthio, (C₁ -C₄)alkylsulfinyl, (C₁ -C₄)alkylsulfonyl, phenyl,amino, mono-N- or di-N,N-(C₁ -C₄)alkylamino, carboxyl, (C₁-C₄)alkoxycarbonyl, carbamoyl, mono-N- or di-N,N-(C₁ -C₄)alkylcarbamoyl,(C₁ -C₄)alkanoylamino, fluorinated (C₁ -C₄)alkanoylamino having from 1to 9 fluorines, (C₁ -C₄)alkylsulfonylamino or fluorinated (C₁-C₄)alkylsulfonylamino having from 1 to 9 fluorines, wherein R₁ and R₂can be taken together to form a five, six or seven membered carbocyclicring or can be taken together to form methylenedioxyl, ethylenedioxyl orpropylenedioxyl and such rings formed by taking R₁ and R₂ together arefused at the 7 and 8 positions; Z is carboxyl, (C₁ -C₄)alkoxycarbonyl,hydroxyaminocarbonyl, -C(O)N(H)SO₂ R₅, tetrazol-5-yl,4,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl, tetrazol-5-yl-aminocarbonyl,3-oxoisoxazolidin-4yl-aminocarbonyl, ##STR20## T forms a five to sevenmembered mono-aza, saturated ring optionally substituted with hydroxyl;and V is --CO₂ R₇, tetrazol-5-yl,4,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl, tetrazol-5-yl-aminocarbonyl or3-oxoisoxazolidin-4-yl-aminocarbonyl.
 3. A compound as recited in claim2 whereinthe C³ and C⁵ substituents are trans; R₁ and R₂ are eachindependently hydrogen, halo, (C₁ -C₄)alkyl, (C₁ -C₄)alkoxy, hydroxy,trifluoromethyl, (C₁ -C₄)alkylthio, fluorinated (C₁ -C₄)alkoxy havingfrom 1 to 9 fluorines, (C₁ -C₄)alkanoyl or R₁ and R₂ taken together forman ethylenedioxy ring; R₃ and R₉ are H; X is oxy; Y is carbonyl; V is--CO₂ R₇ ; and Z is carboxyl, tetrazol-5-yl, ##STR21##
 4. A compound asrecited in claim 3 whereinR₁ and R₂ are each independently hydrogen,halo, (C₁ -C₄)alkyl, (C₁ -C₄)alkoxy, hydroxy or trifluoromethyl; and Zis carboxyl, ##STR22##
 5. A compound as recited in claim 4 whereinTforms a piperidin-1-yl ring; and R₈ is carboxyl or alkylthio.
 6. Thecompound as recited in claim 5 whereinR₄ is neopentyl; R₁ is 7-chloro;R₂ is H; and Z is carboxyl.
 7. The compound as recited in claim 6wherein the stereoisomeris(-)-trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-aceticacid.
 8. The compound as recited in claim 5 whereinR₄ is neopentyl; R₁is 7-chloro; R₂ is H; and Z is 4-carboxylpiperidin-1-yl-carbonyl.
 9. Thecompound as recited in claim 8 wherein the stereoisomeris(-)-N-(trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl)-isonipecoticacid.
 10. The compound as recited in claim 5 whereinR₄ is neopentyl; R₁is 7-chloro; R₂ is H; and Z is 3-carboxylpiperidin-1-yl-carbonyl. 11.The compound as recited in claim 10 wherein the stereoisomeris(-)-N-(trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl)-nipecoticacid.
 12. The compound as recited in claim 11 wherein said compoundis(-)-N-trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl!-(-)-nipecoticacid.
 13. The compound as recited in claim 5 whereinR₄ is neopentyl; R₁is 7-chloro; R₂ is H; V is --CO₂ R₇ ; Z is ##STR23## R₇ is methyl; R₈ iscarboxyl; and p is
 1. 14. The compound as recited in claim 13 whereinthe stereoisomeris(-)-N-(trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl)-L-asparticacid-α-methyl ester.
 15. The compound as recited in claim 5 whereinR₄ isneopentyl; R₁ is 7-chloro; R₂ is H; V is --CO₂ R₇ ; Z is ##STR24## R₇ ismethyl; R₈ is carboxyl; and p is
 2. 16. The compound as recited in claim15 wherein the stereoisomeris(-)-N-(trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl)-L-glutamic-α-methylester.
 17. The compound as recited in claim 5 whereinR₄ is neopentyl; R₁is 7-chloro; R₂ is H; and V is --CO₂ R₇ ; Z is ##STR25## R₇ is H; R₈ isthiomethyl; and p is
 1. 18. The compound as recited in claim 17 whereinthe stereoisomeris(-)-N-(trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl)-L-S-methylcysteine.19. The compound as recited in claim 5 whereinR₄ is neopentyl; R₁ is7-chloro; R₂ is H; and Z is 4-ethoxycarbonylpiperidin-1-yl-carbonyl. 20.The compound as recited in claim 19 wherein the stereoisomer isEthylester of(-)-N-trans-(7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl)-isonipecoticacid.
 21. A compound as recited in claim 5 wherein said compound isN-trans-7-trifluoromethyl-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl!isonipecoticacid; N-trans-7-trifluoromethyl-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl!nipecoticacid; N-trans-7-trifluoromethyl-5-(l-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl!-L-proline;trans-7-methyl-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-aceticacid; N-trans-7-methyl-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-acetyl!isonipecoticacid; N-trans-7-methyl-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5tetrahydro-2-oxo-4,1-benzoxazepine-3-acetyl!nipecoticacid;trans-7-methoxy-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-aceticacid; N-trans-7-methoxy-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-acetyl!isonipecoticacid; or N-trans-7-methoxy-5-(naphthaien-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-acetyl!nipecoticacid.
 22. A compound as recited in claim 5 wherein said compoundis(-)-trans-7-trifluoromethyl-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-aceticacid; (-)-N-trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl!-L-pipecolinicacid; or (-)-N-trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-acetyl)-L-methionine.23. A compound as recited in claim 3 wherein said compoundistrans-7-methylthio-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-4-aceticacid;trans-7-trifluoromethoxy-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-aceticacid;trans-7,8-ethylenedioxy-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-aceticacid; N-trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl!-1-amino-1-cyclopentanecarboxylicacid; N-trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acety3l-1-amino-1-cyclopropanecarboxylicacid; or N-trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl!4-azetidinecarboxylicacid.
 24. A compound as recited in claim 1 wherein T forms a1,3-thiazolidine ring.
 25. The compound as recited in claim 24 whereinsaid compound is(-)-N-trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepin-3-acetyl!-(R)-thiazolidinecarboxylicacid.
 26. A compound as recited in claim 4 whereinT forms apyrrolidin-1-yl ring.
 27. The compound as recited in claim 26 whereinR₄is neopentyl; R₁ is 7-chloro; R₂ is H; and Z is L-proline-N-carbonyl orD-proline-N-carbonyl.
 28. The compound as recited in claim 27 whereinthe compoundis(-)-N-(trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl)-L-proline.29. The compound as recited in claim 27 wherein said compound is(-)-N-trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl!-D-proline.30. A compound as recited in claim 2 whereinthe C³ and C⁵ substituentsare trans; R₁ and R₂ are each independently hydrogen, halo, (C₁-C₄)alkyl, (C₁ -C₄)alkoxy, hydroxy or trifluoromethyl; R₃ and R₉ are H;X is oxy; Y is methylene; V is --CO₂ R₇ ; and Z is carboxyl, ##STR26##31. A compound as recited in claim 30 whereinZ is ##STR27## and T formsa piperidin-1-yl ring.
 32. The compound as recited in claim 31 whereinR₄is neopentyl; R₁ is 7-chloro; R₂ is H; and Z is3-carboxylpiperidin-1-yl-carbonyl.
 33. The compound as recited in claim32 wherein the stereoisomeris(-)-N-(trans-7-chloro-5-(1-naphthyl)-1-neopentyl-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-acetyl)-nipecoticacid.
 34. The compound as recited in claim 31 whereinR₄ is neopentyl; R₁is 7-chloro; R₂ is H; and Z is 4-carboxylpiperidin-1-yl-carbonyl. 35.The compound as recited in claim 34 wherein the stereolsomeris(-)-N-(trans-7-chloro-5-(1-naphthyl)-1-neopentyl-1,2,3,5-tetrahydro-4,1-enzoxazepin-3-acetyl)-isonipecoticacid.
 36. A compound as recited in claim 2 wherein the C³ and C⁵substituents are trans;R₁ and R₂ are each independently hydrogen, halo,(C₁ -C₄)alkyl, (C₁ -C₄)alkoxy, hydroxy, trifluoromethyl, (C₁-C₄)alkyithio, fluorinated (C₁ -C₄)alkoxy having from 1 to 9 fluorines,(C₁ -C₄)alkanoyl or R₁ and R₂ taken together form an ethylenedioxy ring;R₃ and R₉ are H; X is thio; Y is carbonyl; V is --CO₂ R₇ ortetrazol-5-yl; and Z is carboxyl, tetrazol-5-yl, ##STR28##
 37. Acompound as recited in claim 36 whereinT forms a piperidin-1-yl ring.38. A compound as recited in claim 37 wherein said compoundistrans-7-acetyl-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzothiazepine-3-aceticacid; N-trans-7-acetyl-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzothiazepine-3-acetyl!isonipecoticacid;trans-7-chloro5(naphthalen-1-yl)-1-neopentyl-3-(1H-tetrazol-5-ylmethyl)-1,2,3,5-tetrahydro-4,1-benzothiazepin-2-one;or trans-7-chloro-5-(naphthalen-1-yl)-1-neopentyl-3-{2-oxo-2-4-(1H-tetrazol-5-yl)-piperidin-1-yl!-ethyl}-1,2,3,5-tetrahydro-4,1-benzothiazepin-2-one.39. A compound as recited in claim 2 whereinthe C³ and C⁵ substituentsare trans; R₁ and R₂ are each independently hydrogen, halo, (C₁-C₄)alkyl, (C₁ -C₄)alkoxy, hydroxy or trifluoromethyl; R₃ and R₉ are H;X is thio; Y is carbonyl; V is CO₂ -R₇ ; and Z is carboxyl, ##STR29##40. A compound as recited in claim 39 whereinT forms a piperidin-1-ylring.
 41. A compound as recited in claim 40 wherein the compoundistrans-7-methyl-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzothiazepine-3-aceticacid; N-trans-7-methyl-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzothiazepine-3-acetyl!isonipecoticacid; N-trans-7-methyl-5-(naphthaien-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzothiazepine-3-acetyl!nipecoticacid;trans-7-methoxy-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzothiazepine-3-aceticacid; or N-trans-7-methoxy-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzothiazepine-3-acetyl!isonipecoticacid.
 42. The compound as recited in claim 40 whereinR₄ is neopentyl; R₁is 7-chloro; R₂ is H; and Z is 3-carboxylpiperidin-1-yl-carbonyl. 43.The compound as recited in claim 42 wherein the stereoisomeris(-)-N-(trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepin-3-acetyl)-nipecoticacid.
 44. The compound as recited in claim 40 whereinR₄ is neopentyl; R₁is 7-chloro; R₂ is H; and Z is 4-ethoxycarbonylpiperidin-1-yl-carbonyl.45. The compound as recited in claim 44 wherein the stereolsomer isEthylester of(-)-N-(trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepin-3-acetyl)isonipecoticacid.
 46. The compound as recited in claim 40 whereinR₄ is neopentyl; R₁is 7-chloro; R₂ isH;and Z is 4-carboxylpiperldin-1-yl-carbonyl.
 47. Thecompound as recited in claim 46 wherein the stereoisomeris(-)-N-(trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepin-3-acetyl)-isonipecoticacid.
 48. The compound as recited in claim 39 whereinR₄ is neopentyl; R₁is 7-chloro; R₂ is H; and Z is carboxyl.
 49. The compound as recited inclaim 48 wherein the stereolsomeris(-)-trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepin-3-aceticacid.
 50. The compound as recited in claim 49 wherein the compound isthe (R)-α-methylbenzylammonium salt.
 51. The compound as recited in 39whereinR₄ is neopentyl; R₁ is 7-chloro; R₂ is H; V is --CO₂ R₇ ; Z is##STR30## R₇ is methyl; R₁ is carboxyl; and p is
 2. 52. The compound asrecited in claim 51 wherein the stereoisomeris(-)-N-(trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepin-3-acetyl)-L-glutamicacid-α-methyl ester.
 53. The compound as recited in claim 39 whereinR₄is neopentyl; R₁ is 7-chloro; R₂ is H; V is --CO₂ R₇ ; Z is ##STR31## R₇is methyl; R₈ is carboxyl; and p is
 1. 54. The compound as recited inclaim 53 wherein the stereoisomeris(-)-N-(trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepin-3-acetyl)-L-asparticacid-α-methyl ester.
 55. The compound as recited in claim 39 whereinR₄is neopentyl; R₁ is 7-chloro; R₂ is H; V is --CO₂ R₇ ; Z is ##STR32## R₇is H; R₈ is thiomethyl; and p is
 1. 56. The compound as recited in claim55 wherein the stereoisomeris(-)-N-(trans-7-chloro-S-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepin-3-acetyl)-L-S-methylcysteine.57. A compound as recited in claim 39 whereinT forms a pyrrolidin-1-ylring.
 58. A compound as recited in claim 57 whereinR₄ is neopentyl; R₁is 7-chloro; R₂ is H; and Z is L-proline-N-carbonyl or D-proline-Ncarbonyl.
 59. The compound as recited in claim 58 wherein thestereoisomeris(-)-N-(trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepin-3-acetyl)-L-proline.60. The compound as recited in claim 58 wherein the compound is(-)-N-trans-7-chloro-5-(1-naphthyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzothiazepin-3-acetyl!-D-proline.61. A compound as recited in claim 2 whereinthe C³ and C⁵ substituentsare trans; R₁ and R₂ are each independently hydrogen, halo, (C₁-C₄)alkyl, (C₁ -C₄)alkoxy, hydroxy, trifluoromethyl, (C₁ -C₄)alkylthio,fluorinated (C₁ -C₄)alkoxy having from 1 to 9 iluorines, (C₁-C₄)alkanoyl or R₁ and R₂ taken together form an ethylenedioxy ring; R₃is H; R₉ is (C₁ -C₄)alkoxy X is oxy; Y is carbonyl; V is --CO₂ R₇ ortetrazol-5-yl; and Z is carboxyl, tetrazol-5-yl, ##STR33##
 62. Acompound as recited in claim 61 whereinR₁ is 7-chloro; R₂ is H; R₄ isneopentyl; R₉ is methoxy; and T forms a piperidin-1-yl ring.
 63. Acompound as recited in claim 62 wherein the compoundistrans-7-chloro-5-(4-methoxynaphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-aceticacid; N-trans-7-chloro-5-(4-methoxynaphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-acetyl!isonipecoticacid; or N-trans-7-chloro-5-(4-methoxynaphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-acetyl!nipecoticacid.
 64. A method of treating hypercholesterolemia which comprisesadministering to a mammal in need of such treatment ahypercholesterolemic treating amount of a compound of claim
 1. 65. Amethod of treating atherosclerosis which comprises administering to amammal in need of such treatment a atherosclerosis treating amount of acompound of claim
 1. 66. A method for the antifungal treatment of amammal in need of such treatment which comprises administering to themammal an antifungal treating effective amount of a compound of claim 1.67. A method for the treatment of acne In a mammal in need of suchtreatment which comprises administering to the mammal an acne treatingamount of a compound of claim 1.